Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and/or p56lck tyrosine kinases

ABSTRACT

This invention is directed to quinoline/quinoxaline compounds which inhibit platelet-derived growth factor or p56 lck  tyrosine kinase activity, to pharmaceutical compositions comprising these compounds, and to the use of these compounds for treating a patient suffering from or subject to disorders/conditions involving cellular differentiation, proliferation, extracellular matrix production or mediator release and/or T cell activation and proliferation.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a divisional of U.S. Ser. No. 09/198,720 filed Nov. 24, 1998,now U.S. Pat. No. 6,245,760, which in turn is a continuation-in-part ofInternational Patent Application No. PCT/US98/11000, filed May 28, 1998,which in turn is a continuation-in-part of U.S. Ser. No. 08/972,614,filed Nov. 18, 1997, now abandoned, which in turn is acontinuation-in-part of U.S. Ser. No. 08/864,455, filed May 28, 1997,now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to the inhibition of cell proliferationand/or cell matrix production and/or cell movement (chemotaxis) and/or Tcell activation and proliferation using of quinoline/quinoxalinecompounds which are useful protein tvrosine kinase inhibitors (TKIs).

Cellular signaling is mediated through a system of interactions whichinclude cell-cell contact or cell-matrix contact or extracellularreceptor-substrate contact. The extracellular signal is oftencommunicated to other parts of the cell via a tyrosine kinase mediatedphosphorylation event which affects substrate proteins downstream of thecell membrane bound signaling complex. A specific set ofreceptor-enzymes such as the insulin receptor, epidermal growth factorreceptor (EGF-R) or platelet-derived growth factor receptor (PDGF-R) areexamples of tyrosine kinase enzymes which are involved in cellularsignaling. Autophosphorylation of the enzyme is required for efficientenzyme-mediated phosphorylation of substrate proteins containingtyrosine residues. These substrates are known to be responsible for avariety of cellular events including cellular proliferation, cellularmatrix production, cellular migration and apoptosis to name a few.

It is understood that a large number of disease states are caused byeither uncontrolled reproduction of cells or overproduction of matrix orpoorly regulated programmed cell death (apoptosis). These disease statesinvolve a variety of cell types and include disorders such as leukemia,cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases,fibrotic diseases, atherosclerosis and restenosis occurring subsequentto angioplasty of the coronary, femoral or kidney arteries or,fibroproliferative disease such as in arthritis, fibrosis of the lung,kidney and liver. In addition, deregulated cellular proliferativeconditions follow from coronary bypass surgery. The inhibition oftyrosine kinase activity is believed to have utility in the control ofuncontrolled reproduction of cells or overproduction of matrix or poorlyregulated programmed cell death (apoptosis).

It is also known that certain tyrosine kinase inhibitors can interactwith more than one type of tyrosine kinase enzyme. Several tyrosinekinase enzymes are critical for the normal function of the body. Forinstance, it would be undesirable to inhibit insulin action in mostnormal circumstances. Therefore, compounds which inhibit PDGF-R tyrosinekinase activity at concentrations less than the concentrations effectivein inhibiting the insulin receptor kinase could provide valuable agentsfor the selective treatment of diseases characterized by cellproliferation and/or cell matrix production and/or cell movement(chemotaxis) such as restenosis.

This invention relates to the modulation and/or inhibition of cellsignaling, cell proliferation, extracellular matrix production,chemotaxis, the control of abnormal cell growth and cell inflammatoryresponse. More specifically, this invention relates to the use ofsubstituted quinoxaline compounds which exhibit selective inhibition ofdifferentiation, proliferation or mediator release by effectivelyinhibiting platelet-derived growth factor-receptor (PDGF-R) tyrosinekinase activity and/or Lck tyrosinie kinase activity.

2. Reported Developments

A number of literature reports describe tyrosine kinase inhibitors whichare selective for tyrosine kinase receptor enzymes such as EGF-R orPDGF-R or non-receptor cytosolic tyrosine kinase enzymes such as v-ablp56lck or c-src. Recent reviews by Spada and Myers (Exp. Opin. Ther.Patents 1995, 5(8), 805) and Bridges (Exp. Opin. Ther. Patents 1995,5(12), 1245) summarize the literature for tyrosine kinase inhibitors andEGF-R selective inhibitors respectively. Additionally Law and Lydon havesummarized the anticancer potential of tyrosine kinase inhibitors(Emerging Drugs: The Prospect For Improved Medicines 1996, 241-260).

Known inhibitors of PDGF-R tyrosine kinase activity includesquinoline-based inhibitors reported by Maguire et al. (J. Med. Chem.1994, 37, 2129), and by Dolle et al. (J. Med. Clem. 1994, 37, 2627). Aclass of phenylamino-pyrimidine-based inhibitors was recently reportedby Traxler et al. in EP 564409 and by Zimmerman, J.; and Traxler. P. etal. (Biorg. & Med. Chem. Lett. 1996, 6(11), 1221-1226) and byBuchdunger, E. et al. (Proc. Nat. Acad. Sci. 1995, 92, 2558). Despitethe progress in the field there are no agents from these classes ofcompounds that have been approved for use in humans for treatingproliferative disease.

The correlation between the multifactorial disease of restenosis withPDGF and PDGF-R is well-documented throughout the scientific literature.However, recent developments into the understanding of fibrotic diseasesof the lung (Antoniades, H. N.; et al. J. Clin. Invest. 1990, 86, 1055),kidney and liver (Peterson, T. C. Hepatology, 1993, 17, 486) have alsoimplicated PDGF and PDGF-R as playing a role. For instanceglomerulonephritis is a major cause of renal failure and PDGF has beenidentified to be a potent mitogen for mesangial cells in vitro asdemonstrated by Shultz et al. (Am. J. Physiol. 1988, 255, F674) and byFloege, et al. (Clin. Exp. Immun. 1991, 86, 334). It has been reportedby Thornton, S. C.; et al. (Clin. Exp. Immun. 1991, 86, 79) thatTNF-alpha and PDGF (obtained from human rheumatoid arthritis patients)are the major cytokines involved in proliferation of synovial cells.Furthermore, specific tumor cell types have been identified (see Silver,B. J., BioFactors, 1992, 3, 217) such as glioblastoma and Kaposi'ssarcoma which overexpress either the PDGF protein or receptor thusleading to the uncontrolled growth of cancer cells via an autocrine orparacrine mechanism. Therefore, it is anticipated that a PDGF tyrosinekinase inhibitor would be useful in treating a variety of seeminglyunrelated human disease conditions that can be characterized by theinvolvement of PDGF and or PDGF-R in their etiology.

The role of various non-receptor tyrosine kinases such as p56^(lck)(hereinafter “Lck”) in inflammation-related conditions involving T cellactivation and proliferation has been reviewed by Hanke, et al (Inflamm.Res. 1995, 44, 357) and by Bolen and Brugge (Ann. Rev. Immunol., 1997,15, 371). These inflammatory conditions include allergy, autoimmunedisease, rheumatoid arthritis and transplant rejection. Another recentreview summarizes various classes of tyrosine kinase inhibitorsincluding compounds having Lek inhibitory activity (Groundwater, et. alProgress in Medicinal Chemistry, 1996, 33, 233). Inhibitors of Lcktyrosine kinase activity include several natural products which aregenerally non-selective tyrosine kinase inhibitors such asstaurosporine, genistein, certain flavones and erbstatin. Damnacantholwas recently reported to be a low nM inhibitor of Lck (Faltynek, et. al,Biochemistry, 1995, 34, 12404). Examples of synthetic Lck inhibitorsinclude: a series of dihydroxy-isoquinoline inhibitors reported ashaving low micromolai to submicromolar activity (Burke, et. al J. Med.Chem. 1993, 36, 425); and a quinoline derivative found to be much lessactive having an Lck IC₅₀ of 610 micromolar. Researchers have alsodisclosed a series of 4-substituted quinazolines that inhibit Lck in thelow micromolar to submicromolar range (Myers et al. WO95/15758 andMyers, et. al Bioorg. Med. Chem. Lett. 1997, 7.417). Researchers atPfizer (Hanke, et. al J. Biol. Chem. 1996, 271, 695) have disclosed twvospecific pyrazolopyrimidine inhibitors known as PP1 and PP2 which havelow nanomolar potency against Lck and Fyn. (another Src-family kinase).No Lck inhibitory has been reported regarding quinoline or quinoxalinebased compounds. Therefore, it is anticipated that a quinoline orquinoxaline based inhibitor of Lck tyrosine kinase activity could beuseful in treating a variety of seemingly unrelated human diseaseconditions that can be characterized by the involvement of Lek tyrosinekinase signaling in their etiology.

SUMMARY OF THE INVENTION

This invention is directed to a compound of formula I:

wherein

X is L₁OH or L₂Z₂;

L₁ is (CR_(3a)R_(3b))₁ or (CR_(3a)R_(3b))_(m)—Z₃—(CR_(3′a)R_(3′b))_(n);

L₂ is (CR_(3a)R_(3b))_(p)—Z₄—(CR_(3′a)R_(3′b))_(q) or ethenyl;

Z₁ is CH or N;

Z₂ is optionally substituted hydroxycycloalkyl, optionally substitutedhydroxycycloalkenyl, optionally substituted hydroxyheterocyclyl oroptionally substituted hydroxyheterocyclenyl;

Z₃ is O, NR₄, S, SO or SO₂;

Z₄ is O, NR₄, S, SO, SO₂ or a bond;

m is 0 or 1;

n is 2 or 3, and n+m=2 or 3;

p and q are independently 0, 1, 2, 3 or 4, and p+q=0, 1, 2, 3 or 4 whenZ₄ is a bond, and p+q=0, 1, 2 or 3 when Z₄ is other than a bond:

r is 2, 3 or 4;

R_(1a) and R_(1b) are independently optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl, hydroxy,acyloxy, optionally substituted alkoxy, optionally substitutedcycloalkyloxy, optionally substituted heterocyclyloxy, optionallysubstituted heterocyclylcarbonyloxy, optionally substituted atyloxy,optionally substituted heteroaryloxy, cyano, R₅R₆N— or acyl R₅N—, or oneof R_(1a) and R_(1b) is hydrogen or halo and the other is optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionallysubstituted cycloalkyloxy, optionally substituted heterocyclyloxy,optionally substituted heterocyclylcarbonyloxy, optionally substitutedarvloxy, optionally substituted heteroaryloxy, cyano, R₅R₆N— or acylR₅N—.

R_(1c) is hydrogen, optionally substituted alkyl optionally substitutedaryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionallysubstituted alkoxy, optionally substituted cycloalkyloxy optionallysubstituted heterocyclyloxy, optionally substitutedheterocyclylcarbonyloxy, optionally substituted aryloxy, optionallysubstituted heteroaryloxy, halo, cyano, R₅R₆N— or acyl R₅N—;

R_(3a), R_(3b), R_(3′a) and R_(3′b) are independently hydrogen or alkyl:

R₄ is hydrogen, alkyl or acyl; and

R₅ and R₆ are independently hydrogen or alkyl, or R₅ and R₆ takentogether with the nitrogen atom to which R₅ and R₆ are attached formazaheterocyclyl, or

an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof,or pharmaceutically acceptable salt thereof.

Another aspect of the invention is directed to a pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof formula I and a pharmaceutically acceptable carrier. The invention isalso directed to intermediates usefuil in preparing compounds of formulaI, methods for the preparation of the intermediates and compounds offormula I, and the use of a compound of formula I for treating a patientsuffering from or subject to disorders/conditions involving cellulardifferentiation, proliferation, extracellular matrix production ormediator release.

DETAILED DESCRIPTION OF THE INVENTION

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings:

Definitions

“Patient” includes both human and other mammals.

“Effective amount” means an amount of compound of the present inventioneffective in inhibiting PDGF-R tyrosine kinase activity and/or Lcktyrosine kinase activity, and thus producing the desired therapeuticeffect.

“Alkyl” means aliphatic hydrocarbon group which may be branched-orstraight-chained having about 1 to about 10 carbon atoms. Preferredalkyl is “lower-alkyl” having about 1 to about 6 carbon atoms. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl are attached to a linear alkyl chain. The alkyl group is alsooptionally substituted by alkoxyv halo, carboxy, hydroxy or R₅R₆N—.Examples of alkyl include methyl, fluoromethyl, difluorom ethyl,trifluoromethyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, t-butyl,amyl and hexyl.

“Alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 10 carbon atoms in the chain. Preferred alkenyl groupshave 2 to about 6 carbon atoms in the chain; and more preferably about 2to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl or propyl are attached to alinear alkenyl chain. “Lower alkenyl” means about 2 to about 4 carbonatoms in the chain which may be straight or branched. The alkenyl groupmay be substituted by carbalkoxy. Exemplary alkenyl groups includeethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl,heptenyl, octenyl, cyclohexylbutenyl and decenyl.

“Ethylenyl” means a —CH═CH— group.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring system ofabout 3 to about 10 carbon atoms. The cycloalkyl group may besubstituted by one or more, preferably one to three, more preferably oneto two, of the following “cycloalkyl substitlients”, alkyl, hydroxy,acyloxy, alkoxy, halo, R₅R₆N—, acyl R₅N—, carboxy or R₅R₆NCO—,substituents, more preferred substituents are alkyl, hydroxy, acyloxy,alkoxy, and R₅R₆NCO—. Furthermore, when the cycloalkyl group issubstituted with at least two hydroxy substituents, then at least two ofthe liydroxy substituents may be ketalated or acetalated with analdehyde or ketone of one to six carbon atoms to form the correspondingketal or acetal. “Hydroxycycloalkyl” means HO-cycloalkyl wherein thecycloalkyl may be substituted as noted. When the hydroxycycloalkyl groupis derived from a cycloalkyl group which is also substituted withhydroxy, two of the hydroxy substituents may be ketalated or acetalatedwith an aldehyde or ketone of one to six carbon atoms to form thecorresponding ketal or acetal. Ketalization of a gem-diol results information of a spiro fused ring system. A preferred spiro cycloalkylring is 1, 4-dioxaspiro[4, 5]dec-8-yl. Preferred unsubstituted orsubstituted monocyclic cycloalkyl rings include cyclopentyl,hydroxycyclopentyl, fluorocyclopentyl, cyclohexyl, hydroxycyclohexyl,hydroxymethylcyclohexyl and cycloheptyl; more preferred arehydroxycyclohexyl and hydroxycyclopentyl. Exemplary multicycliccycloalkyl rings include 1-decalin, adamant-(1- or 2-)yl,[2.2.1]bicycloheptanyl (norbornyl), hydroxy[2.2.1]bicyclolieptanyl(hydroxynorbornyl), [2.2.2]bicyclooctanyl andhydroxy[2.2.2]bicyclooctanyl: more preferred arehydroxy[2.2.1]bicycloheptanyl (hydroxynorbornyl), andhydroxy[2.2.2]bicyclooctanyl.

“Cycloalkenyl” means a non-aromatic monocyclic or multicyclic ringsystem containing a carbon-carbon double bond and having about 3 toabout 10 carbon atoms. The cycloalkenyl group may be substituted by oneor more, preferably one to three, more preferably one to two cycloalkylsubstituents as described above. “Hydroxycycloalkenyl” meansHO-cycloalkenyl wherein the cycloalkyl may be substituted as noted.Preferred unsubstituted or substituted monocyclic cycloalkenyl ringsinclude cyclopentenyl, cyclohexenyl, hydroxycyclopentenyl,hydroxycyclohexenyl and cycloheptenyl; more preferred ishydroxycyclopenitenyl and hydroxycyclohexenyl. Preferred multicycliccycloalkenyl rings include [2.2.1]bicycloheptenyl (norbornenyl) and[2.2.2]bicyclooctenyl.

“Aryl” means aromatic carbocyclic radical containing about 6 to about 10carbon atoms. Exemplary aryl include phenyl or naphthyl, or phenyl ornaphthyl substituted with one or more aryl croup substituents which maybe the same or different, where “aryl group substituent” includeshydrogen hydroxy, halo, alkyl, alkoxy, carboxy, alkoxycarbonyl orY¹Y²NCO-, wherein Y¹ and Y² are independently hydrogen or alkyl.Preferred aryl group substituenits include hydrogen, halo and alkoxy.

“Heteroaryl” means about a 5- to about a 10- membered aromaticmonocyclic or multicyclic hydrocarbon ring system in which one or moreof the carbon atoms in the ring system is/are element(s) other thancarbon, for example nitrogen, oxygen or sulfur. The “heteroaryl” mayalso be substituted by one or more of the above-mentioned “aryl groupsubstituents”. Exemplary heteroaryl groups include substitutedpyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl,isothiazolyl, oxazolyl thiazolyl, pyrazolyl, furazanyl, pyrrolyl,imidazo[2, 1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,benzimidazolyl, benzothienyl, quinolinyl, imidazolyl and isoquinolinyl.“Heterocyclyl” means an about 4 to about 10 member monocyclic ormulticyclic ring system wherein one or more of the atoms in the ringsystem is an element other than carbon chosen amongst nitrogen, oxygenor sulfur. The heterocyclyl group may be substituted by one or more,preferably one to three, more preferably one to two cycloalkylsubstituents as described above. “Hydroxyheterocyclyl” meansHO-heterocyclyl wherein the heterocyclyl may be substituted as noted.“Azaheterocyclyl” means a heterocyclyl as noted herein wherein at leastone of the ring atoms is nitrogen. Exemplary heterocyclyl moietiesinclude quinuclidyl, pentamethylenesulfide, tetrahydropyranyl,tetrahydrothiophenyl, pyrrolidinyl, tetrahydrofuranyl or7-oxabicyclo[2.2.1]heptanyl.

“Heterocyclylcarbonyloxy” means a heterocyclyl group as hefined hereinwhich is attached to the parent molecular moiety through a carbonyloxy(—C(O)O—) group. The heterocyclyly moiety is optionally substituted byone or more, preferably one to three, more preferably one cycloalkylsubstituents as defined above. A representative heterocyclylcarbonyloxyis [1,4′]-bipiperidin-1′-ylcarbonyloxy.

“Heterocyclenyl” means a heterocyclyl ring system as defined hereinwhich contains at least one carbon-carbon or carbon-nitrogen doublebond. The heterocyclenyl group may be substituted by one or more,preferably one to three, more preferably one to two cycloalkylsubstituents as described above. “Hydroxyheterocyclenyl” meansHO-heterocyclenyl wherein the heterocyclenyl may be substituted asnoted. “Azaheterocyclenyl” means a heterocyclenyl as noted hereinwherein at least one of the ring atoms is nitrogen. Representativemonocyclic heterocyclenyl groups include1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl,1, 2, 3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine,3,4-dihydro-2H-pyran, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl,2-pyrazolinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and thelike.

“Acyl” means an H—CO— or alkyl-CO— group in which the alkyl group is aspreviously described. Preferred acyls contain a lower alkyl. Exemplaryacyl groups include formyl, acetyl, propanoyl, 2-metbylpropanoyl,butanoyl and palmitoyl.

“Aroyl” means an aryl-CO— group in which the alkyl group is aspreviously described. Exemplary groups include benzoyl and 1- and2-naphthoyl.

“Alkoxy” means an alkyl—O— group in which the alkyl group is aspreviously described. Preferred alkoxy is “lower alkoxy” having about 1to about 6 carbon atoms. The alkoxy may be optionally substituted by oneor more amino, alkoxy, carboxy, alkoxycarbonyl, carboxyaryl, carbamoylor heterocyclyl groups. Exemplary alkoxy groups include methoxy, ethoxy,n-propoxy. i-propoxy, n-butoxy, heptoxy, 2-(morpholin-4-yl)ethoxy,2-(ethoxy)etlhoxy, 2-(4-methylpiperazin-1-yl)ethoxy, carbamoyl,N-methylcarbamoyl. N,N-dimethylcarbamoyl, carboxymethoxy andmethoxycarbonylmethoxy.

“Cycloalkyloxy” means a cycloalkyl-O— group in which the cycloalkylgroup is as previously described. Exemplary cycloalkyloxy groups includecyclopentyloxy, cyclolhexyloxy, hydrocyclopentyloxy andhydroxycyclohexyloxy.

“Heterocyclyloxy” means a heterocyclyl-O— group in which theheterocyclyl group is as previously described. Exemplary heterocyclyloxygroups include quinuclidyloxy, pentamethylenesultideoxy,tetrahydropyranyloxy, tetrahydrothiophenyloxy, pyrrolidinyloxy,tetrahydrofuranyloxy or 7-oxabicyclo[2.2.1 ]heptanyloxy,hydroxytetrahydropyranyloxy and hydroxy-7-oxabicyclo[2.2.1]heptanyloxy.

“Aryloxy” means aryl-O— group in which the aryl group is as previouslydescribed.

“Heteroaryloxy” means heteroaryl-O— group in which the heteroaryl groupis as previously described.

“Acyloxy” means an acyl-O— group in which the acyl group is aspreviously described.

“Carboxy” means a HO(O)C— (carboxylic acid) group.

“R₅R₆N—” means a substituted or unsubstituted amino group, wherein R₅and R₆ are as previously described. Exemplary groups include amino(H₂N—), methylamino, ethylmethylamino, dimethylamino and diethylamino.

“R₅R₆NCO—” means a substituted or unsubstituted carbamoyl group, whereinR₅ and R₆ are as previously described. Exemplary groups are carbamoyl(H₂NCO—), N-methylcarbamoyl (MeNHCO—) and N,N-dimethylaminocarbamoyl(Me₂NCO—).

“AcylR₅N—” means an acylamino group wherein R₅ and acyl are as definedherein.

“Halo” means fluoro, chloro, bromo, or iodo. Preferred are fluoro,chloro or bromo, and more preferred are fluoro or chloro.

“Prodrug” means a form of the compound of formula I suitable foradministration to a patient without undue toxicity, irritation, allergicresponse, and the like, and effective for their intended use, includingketal, ester and zwitterionic forms. A prodrug is transformed in vivo toyield the parent compound of the above formula, for example byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S.Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Representative solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereintle solvent molecule(s) islare H₂O.

Preferred Embodiments

A preferred compound aspect of the invention is a compound of formula Iwherein

L₁ is (CR_(3a)R_(3b))_(m)—Z₃—(CR_(′a)R_(3′b))_(n);

L₂ is (CR_(3a)R_(3b))_(p)—Z₄—(CR_(3′a)R_(3′b))_(q);

Z₂ is optionally substituted hydroxycycloalkyl or optionally substitutedhydroxyheterocyclyl;

Z₄ is O and NR₄;

m is 0;

n is 2 or 3;

p+q=0 or 1;

R_(1a) and R_(1b) are independently optionally substituted alkyl,optionally substituted alkoxy, optionally substituted cycloalkyloxy,optionally substituted heterocyclyloxy or R₅R₆N, or one of R_(1a) andR_(1b) is hydrogen or halo;

R_(1c) is hydrogen, optionally substituted alkyl or optionallysubstituted alkoxy;

R_(3a), R_(3b), R_(3′a) and R_(3′b) are independently hydrogen or loweralkyl:

R₄ is hydrogen; and

R₅ R₆ taken together with the nitrogen atom to which R₅ and R₆ areattached form azaheterocyclyl, or

an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof,or pharmaceutically acceptable salt thereof.

Another preferred compound aspect of the invention is a compound offormula I wherein

X is L₂Z₂;

L₂ is (CR_(3a)R_(3b))_(p)—Z₄—(CR_(3′a)R_(3′b))_(q);

Z₂ is optionally substituted hydroxycycloalkyl;

Z₄ is O and NR₄;

p is 0;

q is 0 or 1;

R_(1a) and R_(1b) are independently optionally substituted alkyl,optionally substituted alkoxy, optionally substituted cycloalkyloxy oroptionally substituted heterocyclyloxy, or one of R_(1a) and R_(1b) ishydrogen or halo and the other of R_(1a) and R_(1b) is optionallysubstituted alkyl, optionally substituted alkoxy, optionally substitutedcycloalkyloxy or optionally substituted heterocyclyloxy;

R_(1c) is hydrogen;

R_(3′a) and R_(3′b) are independently hydrogen; and

R₄ is hydrogen, or

an N-oxide thereof, hydrate thereof, solvate thereof, prodrug thereof,or pharmaceutically acceptable salt thereof.

Another preferred compound aspect of the invention is a compound offormula I wherein R_(1a) and R_(1b) are independently optionally hydroxysubstituted lower alkyl, hydroxy, lower alkoxy, cycloalkyloxyheterocyclyloxy, or one of R_(1a) and R_(1b) is hydrogen or halo and theother of R_(1a) and R_(1b) is optionally hydroxy substituted loweralkyl, hydroxy, lower alkoxy, cycloalkyloxy, heterocyclyloxy.

Another preferred compound aspect of the invention is a compound offormula I wherein R_(1a) and R_(1b) are independentlyheterocyclylcarbonyloxy or optionally substituted lower alkoxy; morepreferably, the lower alkoxy is methoxy or ethoxy.

Another preferred compound aspect of the invention is a compound offormula I wherein R_(1a) and R_(1b) are lower alkyl; more preferably thelower alkyl is methyl or ethyl.

Another preferred compound aspect of the invention is a compound offormula I wherein one of R_(1a) and R_(1b) is lower alkoxy, and theother of R_(1a) and R_(1b) is halo; more preferably the lower alkoxy ismethoxy or ethoxy, and the halo is chloro or bromo.

Another preferred compound aspect of the invention is a compound offormula I wherein one of R_(1a) and R_(1b) is lower alkyl, and the otherof R_(1a) and R_(1b) is lower alkoxy; more preferably the lower alkoxyis methoxy or ethoxy, and the lower alkyl is methyl or ethyl.

Another preferred compound aspect of the invention is a compound offormula I wherein one of R_(1a) and R_(1b) is lower alkoxy, and theother of R_(1a) and R_(1b) is cycloalkyloxy; more preferably the loweralkoxy is methoxy or ethoxy, and the cycloalkyloxy is cyclopentyloxy orcyclohexyloxy.

Another preferred compound aspect of the invention is a compound offormula I whereein one of R_(1a) and R_(1b) is hydrogen, and the otherof R_(1a) and R_(1b) is lower alkoxy, cycloalkyloxy or heterocyclyloxy;more preferably the lower alkoxy is methoxy or ethoxy, and thecycloalkyloxy is cyclopentyloxy or cyclohexyloxy, and theheterocyclyloxy is furanyloxy.

Another preferred compound aspect of the invention is a compound offormula I wherein R_(1a) and R_(1b) are lower alkoxy wherein the loweralkoxy is optionally substituted with alkoxy, heterocyclyl, carboxy,alkoxycarbonyl or carbamoyl.

Another preferred compound aspect of the invention is a compound offormula I wherein one of R_(1a) and R_(1b) is unsubstituted lower alkoxyand the other of R_(1a) and R_(1b) optionally substitutedheterocyclylcarbonyloxy or is lower alkoxy substituted with alkoxy,heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl.

Another preferred compound aspect of the invention is a compound offormula I wherein one of R_(1a) and R_(1b) is methoxy and the other ofR_(1a) and R_(1b) is [1, 4′]-bipiperadin-1′-ylcarbonyloxy,2-(ethoxy)ethoxy, 2-(4-morpholinyl)ethoxy,2-(4-methylpiperazin-1-yl)ethoxy, carboxymethoxy,methoxycarbonylmetlhoxy, aminocarbonylmethoxy,N-methylaminocarbonylmethoxy or N,N-dimethylaminocarbonylmethoxy.

Another preferred compound aspect of the invention is a compound offormula I wherein R_(1c) is hydrogen, lower alkyl or lower alkoxy; morepreferably the lower alkoxy is methoxy or ethoxy.

Another preferred compound aspect of the invention is a compound offormula I wherein Z₁ is CH.

Another preferred compound aspect of the invention is a compound offormula I wherein Z₁ is N.

Another preferred compound aspect of the invention is a compound offormula I wherein Z₂ is optionally substituted hydroxycycloalkyl.

Another preferred compound aspect of the invention is a compound offormula I wherein p and q are 0.

Another preferred compound aspect of the invention is a compound offormula I wherein p+q=1.

Another preferred compound aspect of the invention is a compound offormula I wherein Z₄ is O.

Another preferred compound aspect of the invention is a compound offormula I wherein Z₄ is O, and p and q are 0.

Another preferred compound aspect of the invention is a compound offormula I wherein Z₄ is O, and p+q=1.

Another preferred compound aspect of the invention is a compound offormula I wherein Z₄ is NR₄.

Another preferred compound aspect of the invention is a compound offormula I wherein Z₄ is NR₄, and p and q are 0.

Another preferred compound aspect of the invention is a compound offormula I wherein Z₄ is NR₄. and m+n=1.

Another preferred compound aspect of the invention is a compound offormula I wherein Z₄ is S.

Another preferred compound aspect of the invention is a compound offormula I wherein Z₄ is S, and p and q are 0.

Another preferred compound aspect of the invention is a compound offormula I wherein Z₄ is S, and

Another preferred compound aspect of the invention is a compound offormula I wherein Z₂ is (hydroxy or alkyl) substitutedhydroxycycloalkyl, more preferred is (lower alkyl)hydroxycycloalkyl.

Preferred compounds according to the invention are selected from thefollowing species:

trans-4-(7-Chloro-6-methoxyquinoxalin-2-ylamino)-cyclohexanol;

trans-4-(6-Chloro-7-methoxyquinoxalin-2-ylamino)-cyclohexanol;

trans-4-(6, 7-Dimethoxyquinoxalin-2-ylamino)-cyclohexanol;

cis-4-(6, 7-Dimethoxyquinoxalin-2-ylamino)-cyclohexanol;

(2endo,5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptan-2-ol;

(2exo,5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptan-2-ol;

(2endo3exo,5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicycio[2.2.1]heptane-2, 3-diol;

cis-2-(6-Methoxyquinoxalin-2-ylamino)-cyclopentanol;

trans-2-(6-Methoxyquinoxalin-2-ylamino)-cyclopentanol;

trans-4-(6-Methoxyquinoxalin-2-ylamino)-cyclohexanol;

[3aR,4S,6R,6aS]-6-(6,7-Dimethoxyquinoxalin-2-ylamino)-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxole-4-carboxylicethylamide;

2-(1,4-Dioxa-spiro[4,5]dec-8-yloxy)-6,7-dimethoxyquinoxaline;

4-(6,7-Dimethoxyquinoxalin-2-yloxymethyl)-cyclohexanol; 11

3-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanol;

4-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanol:

5-(6,7-Dimethoxyquinoxalin-2-yloxy)-bicyclo[2.2.1]heptane-2,3-diol;

(2exo,3exo,5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptane-2,3-diol;

Acetic acid cis-4-(6,7-dimethoxyquinoxalin-2-yloxy)-cyclohexyl ester;

cis-4-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanol:

Dimethyl-carbamic acid 4-(6,7-dimethoxyquinoxalin-2-yloxy)-cyclohexylester;

trans-4-(6,7-Dimethoxy-4-oxyquinoxalin-2-ylamino)-cyclohexanol;

Acetic acid trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)-cyclohexylester;

(2exo,5exo)-5-(6,7)-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]-heptan-2-ol;

(2endo,5exo)-5-(6,7-Dimethoxyquinoline-2-ylamino)-bicyclo[2.2.1]heptan-2-ol;

(2exo,6exo)-6-(6,7-Dimethoxyquinolin-2-ylamino)-bicyclo[2.2.1]heptan-2-ol;

4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;

(2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;

(+)-(2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;

(−)-(2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;

(2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;

(2cis,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;

(2cis,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;

4-(6,7-Dimethylquinoxalin-2-ylamino)cyclohexanol; and

(1S,2R,4S,5R)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-Bicyclo[2.2.1]-heptan-2-ol.

More preferred compounds are the following:

trans-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-cyclohexanol;

cis-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-cyclohexanol;

4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;

(−)-(2trans,4trans)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol;

(2exo,5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptan-2-ol;

trans-4-(7-Chloro-6-methoxyquinoxalin-2-ylamino)-cyclohexanol; and

4-(6,7-Dimethoxyquinolin-3-ylamino)-cyclohexanol; and

(1S,2R,4S,5R)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-Bicyclo[2.2.1]-heptan-2-ol.

It is to be understood that this invention covers all appropriatecombinations of the particular and preferred groupings referred toherein.

The compounds of this invention may be prepared by employing proceduresknown in the literature starting from known compounds or readilyprepared intermediates. Exemplary general procedures follow.

In addition, compounds of formula I are prepared according to thefollowing Schemes I-X herein the variables are as described above,excepting those variables which one skilled in the art would appreciatewould be incongruent with the method described.

I. General Procedures:

1. Coupling of 2-chloro substituted quinoxaline and amines or anilines

A mixture of 2-chloro-6,7-dimethoxyquinoxaline (1 eq.) and an amine(about 1 to about 5 eq.) is heated at about 160 to about 180° C. fromabout three hours to overnight. The dark-brown residue is dissolved inmethanol/ methylene chloride (0%-10%) and chromatographed on silica geleluted with hexane/ethyl acetate or methanol/methylene chloride(0%-100%) to yield the desired product. The desired product may bepurified further through recrystallization in methanol, methylenechloride or methanol/water.

2. Coupling of 2-chloro substituted quinoxaline and alcohols or phenols

A suspension of an alcohol or mercaptan (1 eq.) and sodium hydride(about 1 to about 3 eq.) in anhydrous DMF/THF (0%-50%) is refluxed for 1hour before addition of 2-chloro-6,7-dimethoxyquinoxaline (1 eq.). Theresulting mixture is refluxed for about one to about four hours. Thesuspension is neutralized to about pH 5-8 and partitioned betweenmethylene chloride and brine. The residue after concentration ofmethylene chloride is chromatograplhed on silica gel eluted withhexane/ethyl acetate or methanol/methylene chloride (0%-100%) to givethe desired product.

3. Reductive amination reaction with amino-quinolines and aldehydes orketones.

An appropriately substituted 3-amino quinoline (1 eq.) is stirred with 1eq. of the appropriate aldehyde or ketone in methanol (or anothersuitable solvent mixture) until TLC indicates imine formation iscomplete. Excess NaCNBH₄ or NaBH₄, or another suitable reducing agent isadded and the mixture is stirred until TLC shows consumption of theintermediate imine. The mixture is concentrated and the residue ischromatographed on silica gel with hexane/ethyl acetate (0-100%) orchloroform/methanol (0-20%) to give the desired product.

4. coupling reaction of 3-amino substituted quinolines and bromophenylcompounds.

An appropriately substituted 3-amino quinoline (1 eq.) is stirred with˜1.4 eq. of a strong base such as sodium t-butoxide, 1 eq. of theappropriate bromophenyl compound, and catalytic amounts of2,2′-bis(diphenylphosphino)-1-1′-binaphthyl (S-BINAP) andbis(dibenzylideneacetone)-Palladium (Pd(dba)₂) are mixed in an inertorganic solvent such as toluene under an inert atmosphere such as argonand heated to about 80° C. overnight. The mixture is cooled, dilutedwith a solvent such as ether, filtered, concentrated and chromatographedwith 50% EtOAc/hexane to give the desired product.

5. Ether formation from 3-hydroxy substituted quinolines via Mitsunobuconditions.

A THF solution of an appropriately substituted hydroxyquinoxaline (atabout 0 to about 25° C.) is treated with 1 eq. each of the desiredalcohol triphenylphosphine and finally diethylazodicarboxylate (DEAD) ora suitable equivalent. The reaction progress is monitored via TLC andupon completion of the reaction (about 1 to about 24 hours) the mixtureis concentrated and the residue is chromatographed on silica gel toyield the desired product.

6. Dealkylation of a lower alkoxy substituted quinoline or quinoxalinie,and subsequent alkylation.

An appropriate lower alkoxy substituted quinoline or quinoxaline (1 eq.)in DMF is treated with excess sodium ethanthiolate (usually about 2 ormore eq.) and the reaction mixture is stirred with heating from about 1to about 24 hours. The mixture is partitioned between water and ethylacetate. Extractive a workup followed by chromatography, if necessary,provides the corresponding desired hydroxy substituted quinoline orquinoxaline product.

The hydroxy substituted quinoline or quinoxaline product can bealkylated using the conditions for the Mitsunobu reaction as detailedabove. Alternatively, simple alkylation using methods well-known in theart with a reactive alkyl- or benzyl-halide using NaH or anotherappropriate base in a suitable solvent provides the desired alkylatedproduct.

7. Oxidation of a nitrogen in a quinoline or quinoxaline to thecorresponding N-oxide.

An imine (═N—) moiety in a quinoline or quinoxaline compound of formula(I), may be converted to the corresponding compound wherein the iminemoiety is oxidized to an N-oxide, preferably by reacting with a peracid,for example peracetic acid in acetic acid or m-chloroperoxybenzoic acidin an inert solvent such as dichloromethane, at a temperature from aboutroom temperature to reflux, preferably at elevated temperature.

The compounds of the present invention are useful in the form of thefree base or acid or in the form of a pharmaceutically acceptable saltthereof. All forms are within the scope of the invention.

Where the compound of the present invention is substituted with a basicmoiety, acid addition salts are formed and are simply a more convenientform for use; and in practice, use of the salt form inherently amountsto use of the free base form. The acids which can be used to prepare theacid addition salts include preferably those which produce, whencombined with the free base, pharmaceutically acceptable salts, that is,salts whose anions are non-toxic to the patient in pharmaceutical dosesof the salts, so that the beneficial inhibitory effects on PDGF inherentin the free base are not vitiated by side effects ascribable to theanions. Although pharmaceutically acceptable salts of said basiccompounds are preferred, all acid addition salts are useful as sourcesof the free base form even if the particular salt, per se, is desiredonly as an intermediate product as, for example, when the salt is formedonly for purposes of purification, and identification, or when it isused as intermediate in preparing a pharmaceutically acceptable salt byion exchange procedures. Pharmaceutically acceptable salts within thescope of the invention are those derived from the following acids:mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acidand sulfamic acid; and organic acids such as acetic acid, citric acid,lactic acid, tartaric acid, malonic acid, methanesufonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclohexylsulfamic acid, quinic acid, and the like. The correspondingacid addition salts comprise the following: hydrohalides, e.g.hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate,acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate,propionate, succinate, fuinarate, maleate,methylene-bis-p-hydroxynaphthoates, gentisates, mesylates, isethionatesand di-p-toluoyltartratesmethanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate,respectively.

According to a further feature of the invention, acid addition salts ofthe compounds of this invention are prepared by reaction of the freebase with the appropriate acid, by the application or adaptation ofknown methods. For example, the acid addition salts of the compounds ofthis invention are prepared either by dissolving the free base inaqueous or aqueous-alcohol solution or other suitable solventscontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and acid in an organicsolvent, in which case the salt separates directly or can be obtained byconcentration of the solution.

The compounds of this invention can be regenerated from the acidaddition salts by the application or adaptation of known methods. Forexample, parent compounds of the invention can be regenerated from theiracid addition salts by treatment with an alkali, e.g. aqueous sodiumbicarbonate solution or aqueous ammonia solution.

Where the compound of the invention is substituted with an acidicmoiety, base addition salts may be formed and are simply a moreconvenient form for use; and in practice, use of the salt forminherently amounts to use of the free acid form. The bases which can beused to prepare the base addition salts include preferably those whichproduce, when combined with the free acid, pharmaceutically acceptablesalts, that is, salts whose cations are non-toxic to the animal organismin pharmaceutical doses of the salts, so that the beneficial inhibitoryeffects on PDGF inherent in the free acid are not vitiated by sideeffects ascribable to the cations. Pharmaceutically acceptable salts,including for example alkali and alkaline earth metal salts, within thescope of the invention are those derived firom the following bases:sodium hydride, sodium hydroxide, potassium hydroxide, calciumhydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide,zinc hydroxide, ammonia, trimethylammiionia, triethylammonia,ethylenediamine, n-methyl-glucamine, lysine, arginine, ornithine,choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine,procaine, n-benzylphenethylamine, diethylamine, piperazine,tris(hydroxymethyl)-aminomethane, tetramethylamnmonium hydroxide, andthe like.

Metal salts of compounds of the present invention may be obtained bycontacting a hydride, hydroxide, carbonate or similar reactive compoundof the chosen metal in an aqueous or organic solvent with the free acidform of the compound. The aqueous solvent employed may be water or itmay be a mixture of water with an organic solvent, preferably an alcoholsuch as methanol or ethanol, a ketone such as acetone, an aliphaticether such as tetrahydrofuran, or an ester such as ethyl acetate. Suchreactions are normally conducted at ambient temperature but they may, ifdesired, be conducted with heating.

Amine salts of compounds of the present invention may be obtained bycontacting an amine in an aqueous or organic solvent with the free acidform of the compound. Suitable aqueous solvents include water andmixtures of water with alcohols such as methanol or ethanol, ethers suchas tetrahydrofuran, nitriles such as acetonitrile, or ketones such asacetone. Amino acid salts may be similarly prepared.

The compounds of this invention can be regenerated from the baseaddition salts by the application or adaptation of known methods. Forexample, parent compounds of the invention can be regenerated from theirbase addition salts by treatment with an acid, e.g., hydrochloric acid.

As well as being useful in themselves as active compounds, salts ofcompounds of the invention are useful for the purposes of purificationof the compounds, for example by exploitation of the solubilitydifferences between the salts and the parent compounds, side productsand/or starting materials by techniques well known to those skilled inthe art.

Compounds of the present invention may contain asymmetric centers. Theseasymmetric centers may independently be in either the R or Sconfiguration. It will also be apparent to those skilled in the art thatcertain compounds of formula I may exhibit geometrical isomerism.Geometrical isomers include the cis and trans forms of compounds of theinvention, i.e., compounds having alkenyl moieties or substituents onthe ring systems. In addition, bicyclo ring systems include endo and exoisomers. The present invention comprises the individual geometricalisomers, stereoisomers, enantiomers and mixtures thereof.

Such isomers can be separated from their mixtures, by the application oradaptation of known methods, for example chromatographic techniques andrecrystallization techniques, or they are separately prepared from theappropriate isomers of their intermediates, for example by theapplication or adaptation of methods described herein.

The starting materials and intermediates are prepared by the applicationor adaptation of known methods, for example methods as described in theReference Examples or their obvious chemical equivalents, or by methodsdescribed according to the invention herein.

The present invention is further exemplified but not limited by thefollowina illustrative examples which describe the preparation of thecompounds according to the invention.

Further, the following examples are representative of the processes usedto synthesize the compounds of this invention.

EXAMPLE 1 3-Cyclohexyloxy-6,7-dimethoxyquinoline

To a THF solution (30 mL) at 0° C. is added3-hydroxy-6,7-dimethoxyquinojine (0.237 g, 1.15 mmole), cyclohexanol(0.347 g, 3.46 mmole), Ph₃P (0.908 g, 3.46 mmole).Diethylazodicarboxylate is added portionwise until the solution retaineda deep red color (0.663 g, 3.81 mmole). After 4 hours the solution isconcentrated and the residue chromatographed (50% EtOAc in hexanes). Theproduct is recrystallized from isopropanol/hexanes as the HCl salt as awhite solid (m.p. 229-232° C. dec.).

EXAMPLE 2 2-Anilino-6-isopropoxy-quinoxaline hydrochloride

To NaH (0.033 g, 0.84 mmol) under argon is added 1 mL DMF.2-Anilino-6-quinoxalinol (0.1 g, 0.42 mmol) in 1.5 mL DMF is addedportionwise. After 30 minutes, 2-bromopropane is added dropwise and thesolution is heated to 50° C. for 1.5 hours. The cooled reaction mixtureis quenched with water and partitioned between EtOAc and H₂O, washedwith H₂O (3X), brine, dried (MgSO₄), and concentrated. The resultingresidue is chromatographed (30% EtOAc/hexanes) to provide 0.05 gdialkylated product and 0.1 g of the title compound. An analyticalsample of the HCl salt is obtained by addition of IPA (isopropanol)/HClto an Et₂O/IPA solution of the free base to provide HCl salt (m.p.205-210° C. dec). Anal. Calcd. for C₁₇H₁₇N₃O•HCl: C, 64.65; H, 5.74; N,13.31; Found: C, 64.51 H, 5.90; N, 13.09.

EXAMPLE 3 2-Anilino-6-methoxy-quinoxaline hydrochloride

To 2-cliloro-6-methoxy-quinoxaline (0.93 g, 4.8 mmol) under argon isadded aniline (1.3 mL, 14.3 mmol). The reaction mixture is heated at120° C. for 2 hours, then at 150° C. for 1.5 hours. The mixture iscooled and CH₂Cl₂ is added. The resulting suspension is stirred and theorange solid is filtered off, washed with CH₂Cl₂/Et₂O, then stirredvigorously in H₂O for 40 minutes, filtered, and washed with Et₂O toprovide a bright-yellow solid.

EXAMPLE 4 2-Anilino-6-quinoxalinol

By the method of Feutrill, G. I.; Mirrington, R. N. Tet. Lett. 1970,1327; the aryl methyl ether is converted to the phenol derivative. To2-anilino-6-methoxy-quinoxaline (0.27 g, 1.07 mmol) under argon in DMFis added the sodium salt of ethanethiol (0.19 g, 2 mmol). The reactionmixture is heated to 110° C. overnight. The mixture is concentrated andpartitioned between EtOAc and H₂O/5% tartaric acid such that the pH ofthe aqueous layer is approximately 4. The organic layer is washed with120 (4X), then with 2.5% NaOH (4X). The basic layers combined, washedwith EtOAc (2X), re-acidified with 5% tartaric acid, and washed withmultiple portions of EtOAc. The organic layers are combined, washed withbrine, dried (Na₂SO₄), and concentrated. The resulting solid ischromatographed (50% EtOAc/hexanes). An analytical sample is obtained bytriturating the product with Et₂O to provide a yellow powder (m.p.211-213° C.). Anal. Calcd. for C₁₄H₁₁N₃O: C, 70.88; H, 4.67: N, 17.71;Found: C, 70.64; H, 4.85; N, 17.58.

EXAMPLE 5 Phenyl-[6-(tetrahydrofuran-3-(R)-yl-oxy)quinoxalin-2-yl]amine

To a THF solution at 0° C. under argon is added 2-anilino-6-quinoxalinol(0.23 g, 0.97 mmol), (S)-(+)-3-hydroxytetrahydrofuran (0.086 mL, 1.3mmol), and triplenylphosphine (0.31 g, 1.2 mmol). DEAD (0.18 mL, 1.2mmol) is added portionwise. The reaction is allowed to warm to roomtemperature and stirred for 1.5 hours. The mixture is concentrated andpartitioned between EtOAc and H₂O. The organic layer is washed with H₂O,brine, dried (MgSO₄), and concentrated. The resulting yellow oil ischromatographed (50% EtOAc/hexanes) and taken up in Et₂O/IPA. HCl/ Et₂Osolution is added dropwise and the resulting red-orange powder is driedin vacuo. The powder is free-based by stirring in MeOH with washed (3XH₂O, 5X MeOH) basic ion exchange resin. The mixture is stirred 30minutes, filtered, concentrated, and recrystallized from EtOAc/hexanesto provide, in two crops, the product (m.p. 1703-175° C.). Anal. Calcd.for C₁₈H₁₇N₃O₂: C, 70.35; H, 5.57; N, 13.67; Found: C, 70.19; H, 5.60;N, 13.66.

EXAMPLE 6 2,7-Bis-cyclolhexyloxy-6-methoxy-quinoxaline

To a DMF solution (5 mL) of NaH (0.32 g, 8 mmol) under argon,cyclohexanol (0.7 mL, 6.7 mmol) is added dropwise. The mixture isstirred at room temperature for 25 minutes, then2-chloro-6,7-dimethoxyquinoxaline is added portionwise. The reaction isstirred for 15 minutes at room temperature, at 90° C. for 2 hours, andat 110° C. for 1 hour. The mixture is cooled, quenched with H₂O, andpartitioned between EtOAc/H₂O. The organic layer is washed with H₂O andbrine, dried (MgSO₄), and chromatographed (10% EtOAc/hexanes) to providea waxy white solid (m.p. 75-78° C.). Anal. Calcd. for C₂₁H₂₈N₂O₃: C,70.76; H, 7.92; N, 7.86; Found: C, 70.81; H, 7.79; N, 7.70.

EXAMPLE 7 Cyclohexyl-(6,7-dimethoxyquinoxalin-2-ylmethyl)-amine

To a 0.067 M solution of 6,7-dimethoxy-2-quinoxaline carboxaldehyde in2:1 MeOH/1, 2-dichloroethane (7.5 mL, 0.5 mmol) is added cyclohexylamine(0.11 mL, 0.9 mmol). The reaction is allowed to stir at room temperatureovernight, then NaBH₄ (0.038 g, 1 mmol) is added and the reactionmixture is stirred overnight. The mixture is then concentrated andchromatographed (50% EtOAc/hexanes-approximately 5% MeOH in 50%EtOAc/hexanes). The oil is dissolved in EtOAc/hexanes and treated withHCl in EtOH. The resulting solution is concentrated and the solids aretriturated with isopropanol to provide a white solid after drying invacuo at 60° C. (m.p. 185-190° C., dec.). Anal. Calcd. forC₁₇H₂₃N₃O₂•HCl: C, 60.44; H, 7.16; N, 12.44; Found: C, 60.48; H, 6.88;N, 12.07.

EXAMPLE 8(6,7-Dimetoxyquinolin-3-yl)-trans-(3-(R)-methyl-cyclohexyl)-amine and(6,7-Dimethoxyquinolin-3-yl)-cis-(3-(R)-methyl-cyclohexyl)-amine

The reaction is performed similarly to the above preparation using thefree base of 3-amino-6,7-dimethoxyquinoline (0.32 g, 1.6 mmol) and(R)-(+)-3-methylcyclohexanone (0.23 mL, 1.9 mmol). The product mixtureobtained is chromatographed (70% EtOAc/hexanes), and recrystallized fromEtOAc/hexanes to obtain a white solid (1:1 mixture of cis and transisomers) (m.p. 153-160° C.). Anal. Calcd. for C₁₈H₂₄N₂O₂: C, 71.97; H,8.05; N, 9.33; Found: C, 72.12; H, 7.85; N, 9.29.

EXAMPLE 9 3-(6,7-Dimethoxyquinolin-3-yl-amino)-2,2-dimethyl-propan-1-ol

The reaction is run similar to the preparation in Example 7. To a MeOHsolution of 4 Å powdered molecular sieves (0.35 g) under argon is added3-amino-6,7-dimethoxyquinoline (0.32 g, 1.6 mmol) and2.2-dimethyl-3-hydroxypropionaldelhyde (0.19 g, 1.9 mmol). The productmixture is chromatographed (3% MeOH/CHCl₃) to afford 0.10 g of materialwhich is partitioned between CH₂Cl₂/10% NaOH. The organic layer iswashed with 10% NaOH, H₂O, and brine, then dried (MgSO₄), andrecrystallized from EtOAc/hexanes to provide a light-orange solid (m.p.170-173.5° C.). Anal. Calcd. for C₁₆H₂₂N₂O₃: C, 66.18; H, 7.64; N, 9.65;Found: C. 66.11; H, 7.49; N, 9.33.

EXAMPLE 10 Cyclohexyl-(6-methoxy-7-morpholin-4-yl-quinoxalin-2-yl)-amine

This preparation is based on an adaptation of the method described byBuchwald, et al. J. Am. Chem. Soc., 1996 118, 7215. To a toluenesolution of 2-cyclohexylamino-6-methoxy-7-bromo-quinoxaline (0.1 g, 0.3mmol) under argon is added morpholine (0.1 g. 0.3 mmol), sodiumtert-butoxide (0.04 g, 0.42 mmol), S-(−)-BINAP (cat.. 0.001 g), andbis(dibenzylideneacetone)-palladium (cat., 0.001 g). The reactionmixture is heated to 80° C. overnight. The mixture is cooled, dilutedwith Et₂O, filtered, concentrated, and chromatographed (50%EtOAc/hexanes). The product is recrystallized from EtOAc/hexanes toprovide, in two crops, to provide a yellow solid (m.p. 194-196° C.).Anal. Calcd. for C₁₉H₂₆N₄O₂: C, 66.64; H, 7.65; N, 16.36; Found: C,66.60; H, 7.60; N, 16.51.

EXAMPLE 11 trans-4-(7-Chloro-6-methoxy-quinoxalin-2-amino)-cyclohexanoland trans-4-(6-Chloro-7-methoxy-quinoxalin-2-yl-amino)-cyclohexanol

To a reaction flask under argon fitted with a Dean-Stark trap and acondenser is added 6-1 2, 7-dichloro-6-methoxy-quinoxaline:2,6-dichloro-7-methoxy-quinoxaline (0.30 g, 1.3 mmnol) andtrans-4-amino-cyclohexanol (0.35 g, 3 mmol). The reaction mixture isheated to 170° C. for approximately 10 hours, then concentrated andchromatographed twice, (7% MeOH/CHCl₃, then 5% MeOH/CHCl₃). The productis recrystallized from EtOAc/hexanes to provide a light-yellow solid(m.p. 144-147° C.). Anal. Calcd. for C₁₉H₂₆N₄O₂•0.4H₂O: C, 57.20; H,6.02; N, 13.34; Found: C, 57.21; H, 5.97; N, 13.08.¹H NMR analysisrevealed that the product is a 2:1 mixture oftrans-4-(7-chloro-6-methoxy-quinoxalin-2-amino)-cyclohexanol:trans-4-(6-chloro-7-methoxy-quinoxalin-2-yl-amino)-cyclohexanol.

EXAMPLE 12 trans-4-(6,7-Dimethoxyquinoxalin-2-ylamino)cyclohexanol

trans-4-aminocyclobexanol (0.11 g, 2 eq.) and2-chloro-6,7-dimethoxyquinoxaline (0.1 g, 1 eq.) are combined and heatedto 160-180° C. for a period of 4-8 hours. The dark-brown suspension isfiltered and concentrated. The residue is purified on a flash columneluted with 3% methanol/methylene chloride to provide the product as ayellow powder with m.p. of 119-123° C. Anal. Calcd. for C₁₆H₂₁N₃O₃: C,62.33; H, 7.05; N, 13.63, Found: C, 62.35; H, 7.09; N, 13.18.

The compound could be recrystallized by the following method. Startingwith 0.2 g of yellow powder in a mixture of 2.5 mL of water and 1.25 mLof methanol a clear orange-colored solution is obtained upon reflux. Thehot solution is left standing and cooled gradually. Orange-coloredneedle-like crystals are collected by filtration and dried under highvacuum to give a yellow solid (m.p. 119-120° C.).

Alternatively, the HCl salt of the title compound is prepared asfollows: To a solution oftrans-4-(6,7-dimethoxyquinoxalin-2-ylamino)-cyclohexanol in isopropanolis added a solution of HCl at 0° C. The mixture is stirred for 15minutes before filtation. The solid collected is dried under a highvacuum to provide thetrans-4-(6,7-dimethoxyquinoxalin-2-ylamino)-cyclohexanol hydrochloricacid salt. Anal. Calcd. for C₁₆H₂₂ClN₃O₃•1.2H₂O: C, 53. 19; H, 6.80; N,11.63; Cl, 9.81; Found: C, 53.14: H, 6.85; N, 11.24; Cl, 10.28.

Alternatively, the sulfate salt of the title compound is prepared asfollows: In a typical procedure,trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)-cyclohexanol is dissolved inacetone or another suitable organic solvent with warming up to 45° C. asnecessary. To the resultant solution is carefully added aqueous H₂SO₄ (1equiv., 1 M soln) with rapid stirring. The salt thus formed is collectedand dried to provide the sulfate in >80% yield.

The following compounds are prepared similarly beginning with theappropriate starting material.

3-(6,7-Dimethoxyquinoxalin-2-ylamino)-propan-1-ol (m.p. 154.5-156° C.).Anal. Calcd. for C₁₃H₁₇N₃O₃: C, 59.30 H, 6.51: N, 15.96; Found: C,59.30; H, 6.46: N, 15.87.

3-(6,7-Dimethoxyquinoxalin-2-ylamino)-2, 2-dimethyl-propan-1-ol (m.p.174-176.5° C.). Anal. Calcd. for C₁₅H₂₁N₃O₃: C, 61.84; H, 7.27; N,14.42; Found: C, 61.67; H, 7.22; N, 14.22.

4-(6,7-Dimethylquinoxalin-2-ylamlino)-cyclohexanol (m.p. 168-171° C.).Anal. Calcd. for C₁₆H₂₁N₃O: C, 70.82: H, 7.80; N, 15.48; Found: C,70.76; H, 7.90; N, 15.20.

EXAMPLE 13 cis-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-cyclohexanol

A mixture of cis-4-aminocyclohexanol (400 mg, 3.48 mmole) and2-chloro-6,7-dimethoxyquinoxaline (450 mg, 2 mmole) in 5 mL of ethanolis placed in sealed tube and then heated at 180° C. for 3 hours. Thedark-brown mixture is chromatographed on silica gel and eluted withethyl acetate to provide the desired product (m.p. 65-67° C.). Anal.Calcd. for C₁₆H₂₁N₃O₃•0.6H₂O: C, 61.17; H, 7.12; N, 13.37; Found: C,61.22; H, 7.19; N, 12.19.

EXAMPLE 14(±)-Bicyclo[2.2.1]hept-2-yl-(6,7-dimethoxyquinoxalin-2-yl)-amime

Procedure A: A mixture of 2-chloro-6,7-dimethoxyquinoxaline (5 g, 22.3mmole) and (±)-eco-norbornyl-2-amine (10 g, 90 mmole) is heated at160-180° C. overnight. The dark-brown residue is dissolved in 200 mL ofmethylene chloride and washed with 1 N NaOH (50 mL). The organic layeris dried over magnesium sulfate and then filtered. The residue afterconcentration is chromatographed on silica gel eluted with hexane/ethylacetate (80%) to provide the desired product as a yellow solid which canbe recrystalized in methanol.

Procedure B: A mixture of 2-chloro-6,7-dimethoxyquinoxaline (9 g, 40.1mmole) and (±)-exo-norbornvl-2-amine (5.77 g, 52 mmole), Sodiumt-butoxide (4.22 g, 44 mmole),2,2′-bis(diphenylphosphino)-1-1′-binaphthyl (BINAP, 120 mg) andbis(dibenzylideneacetone)-palladium Pd(dba)₂, 40 mg in 80 mL of tolueneis heated at 80° C. for eight hours. Another portion of BINAP (60 mg)and Pd(dba)₂ (20 mg) is added and the mixture is heated at 100° C.overight. After being diluted with 200 mL of methylene chloride, thereaction mixture is washed with 1N NaOH (100 mL). The organic layer isdried over magnesium sulfate and filtered. The residue afterconcentration is chromatographed on silica gel eluted with hexane/etlhylacetate (80%) to provide the desired product as a light-yellow solid(m.p. 188-189° C.). Anal. Calcd. for C₁₇H₂₁N₃O₃: C, 68.20; H. 7.07; N,14.04; Found: C, 68.18; H, 7.03; N, 14.03.

The following compounds are prepared similarly beginning with theappropriate starting material (procedure A).

exo-bicyclo[2.2.1]hept-5-en-2-yl-(6,7-dimethoxyquinoxalin-2-yl)-amine(in.p. 175-177° C.). Anal. Calcd. for C₁₇H₁₉N₃O₂.0.4 H₂O: C, 60.94; H.6.56; N, 13.78; Found: C, 66.98; H, 6.62; N, 12.73. (2endo,5exo)-5-(6,7-Dimethoxyquiinoxalin-2-ylamino)-bicyclo[2.2.1]heptan-2-ol(m.p. 90-93° C.). (2exo,5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1 ]heptan-2-ol(m.p. 97-100° C). (2endo, 3exo,5exo)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptane-2,3-diol (m.p. 220-222° C.). Anal. Calcd. for C₁₇H₂₁N₃O₄•0.2H₂O: C, 60.96; H, 6.44; N, 12.54; Found: C, 60.93; H, 6.06; N, 11.60.

Cyclohexyl-(6,8-dimethyl-quinoxalin-2-yl)-amine [MS m/z: 255 (M+)].Anal. Calcd. for C₁₆H₂₁N₃: C. 75.26; H, 8.29; N. 16.46; Found: C, 75.08;H, 8.28: N. 15.86.

cis/trans-2-(6-Methoxy-qtiioxalin-2-ylamino)-cyclopentanol (m.p.137-139° C.). Anal. Calcd. for C₁₄H₁₇N₃O₂: C, 64.85: H, 6.61; N. 16.20;Found: C, 64.87:H, 6.45; N, 16.22.

trans-4-(6-Methoxy-quinoxalin-2-ylamino)-cyclohexanol (m.p. 70-75° C.).Anal. Calcd. for C₁₅H₁₉N₃O₂•0.3 H₂O: C. 64.64 1H, 7.09; N, 15.08; Found:C. 64.68: H. 7.06; N, 14.77.

[3aR,4S,6R,6aS]-6-(6,7-Dimethoxyquinoxalin-2-ylamino)-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxole-4-carboxylicethylamide (m.p. 94-97° C.).

Anal. Calcd. for C₂₁H₂₈N₄O₅•0.3 H₂O: C, 59.79; H, 6.83; N, 13.28; Found:C, 59.80; H, 6.89; N, 12.03.(6,7-Dimethoxyquinoxalin-2-yl)-(4-methoxy-cyclohexyl)-amine (m.p. 58-68°C.).

Anal. Calcd. for C₁₇H₂₃N₃O₃•0.5 H₂O: C, 62.56; H, 7.41; N, 12.87; Found:C, 62.53; H, 7.22; N, 12.22.

EXAMPLE 15 exo-2-(Bicyclo[2.2.1]hept-2-yloxy)-6,7-dimethoxyquinoxaline

A mixture of exo-2-norborneol (223 mg, 2 mmole) and NaH (60%, 100 mg,2.5 mmole) in 10 mL of anhydrous THF is refluxed for 0.5 hour beforeaddition of 2-chloro-6,7-dimetloxyquinoxaline (336 mg, 1.5 mmole). Theresulting mixture is continued to refluxed for two hours. The residueafter filtration and concentration is chromatographed on silica gel (50%etherlhexane) to provide the desired product as a white solid (m.p.135-137° C.). Anal. Calcd. for C₁₇H₂₀N₂O₃: C, 67.98; H, 6.71; N, 9.33;Found: C, 67.96; H, 6.762; N, 9.19.

The following compounds are prepared similarly beginning with theappropriate starting material.

exo-2-(Bicyclo[2.2.1]hept-5-en-2-yloxy)-6,7-dimethoxyquinoxaline (m.p.108-110° C.). Anal. Calcd. for C₁₇H₁₈N₂O₃: C, 68.44; H, 6.08; N. 9.39;Found: C. 68.54; H. 6.23; N, 9.27.

2-(Bicyclo[2.2.1]hept-5-en-2-yloxy)-6,7-dimethoxyquinoxaline (m.p.93-95° C.).

Anal. Calcd. for C₁₇H₁₈N₂O₃: C, 68.44; H, 6.08; N, 9.39; Found: C,68.32; H, 5.98; N. 9.25.2-(1,4-Dioxa-spiro[4,5]dec-8-yloxy)-6,7-dimethoxyquinoxaline (in.p.124-125° C.).

Anal. Calcd. for C₁₈H,₂₂N₂O₅: C. 62.42: H 6.40; N, 8.09; Found: C,62.63; H, 6.46; N, 7.79.

EXAMPLE 16 cis/trans-4-(6,7-Dimnethoxyquinoxalin-2-yloxy)-cyclohexanecarboxylic acid.

A mixture of cis/trans-4-hydroxy-cyclohexanecarboxylic acid (144 mg, 1mmole) and NaH (60%, 160 mg 4 mmole) in anhydrous THF/DMF(10 mL/2 mL) isrefluxed for one hour before addition of2-chloro-6,7-dimethoxyquinoxaline (225 mg, 1 mmole). The resultingmixture is continued to refluxed for four hours. The reaction mixture isneutralized to pH 5 and extracted with ethyl acetate (2×50 mL). Thecombined organic solutions are dried over magnesium sulfate andfiltered. The residue after concentration is chromatographed on silicagel (ethyl acetate, followed by methanol) to provide the desired productas a white solid (m.p. 90-93° C.). Anal. Calcd. for C₁₇H₂₀N₂O₅.0.5 H₂O:C, 59.89. H, 6.19; N, 8.22. Found: C. 59.91; H, 6.62; N, 7.90.

The following compounds are prepared similarly beginning with theappropriate starting material4-(6,7-Dimethoxyquinoxalin-2-yloxymethyl)-cyclohexanol (m.p. 118-121°C.). Anal. Calcd. for C₁₇H₂₂N₂O₄•0.3 •H₂O: C. 63.15; H, 7.03: N, 8.66;Found: C, 63.13; H. 6.65; N, 9.01.3-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohlexano](m.p. 151-153° C.).Anal. Calcd. for C₁₆H₂₀N₂O₄: C, 63.14; H, 6.62; N. 9.20: Found: C.62.56. H. 6.58; N, 8.67.4-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanol (m.p. 162-164° C).Anal. Calcd. for C₁₆H₂₀N₂O₄: C, 63.14: H. 6.62; N. 9.20; Found: C,62.52; H, 6.80; N, 8.88.

EXAMPLE 17 5-(6,7-Dimethoxyquinoxalin-2-yloxy)-bicyclo[2.2.1]heptane-2,3-diol

To a solution of2-(bicyclo[2.2.1]hept-5-en-2-yloxy)-607-dimethoxv-quinoxaline (149 mg,0.5 mmole) and 4-methylmoipholine N-oxide (234 mg, 2 mmole) at roomtemperature in 5 mL of THF is added a solution of OsO₄ in t-butanol(2.5% by wt., 0.2 mL). The brown solution is stirred vigorously for twohours before being quenched with saturated NaHS₂O₃ (2 mL). Ether (3×100mL) is used to extract and then dried over magnesium sulfate. Theresidue after filtration and concentration is chromatographed on silicagel (50% ethyl acetate/hexane) to provide the desired product (m.p.85-88° C.). Anal. Calcd. for C₁₇H₂₀N₂O₅•0.9 H₂O: C, 58.73; H, 6.29; N,8.06; Found: C, 58.74; H, 5.91; N, 7.53.

Prepared similarly is (2exo, 3exo,5exo)-5-(6,7-dimethoxyquinoxalin-2-ylamino)-bicyclo[2.2.1]heptane-2,3-diol(m.p. 150-153° C.).

EXAMPLE 18

Acetic acid cis-4-(6,7-dimethoxyquinoxalin-2-yloxy)-cyclohexyl ester andcis-4-(6,7-dimethoxyquinoxalin-2-yloxy)-cyclohexanol

A mixture of cis 4-acetoxy-cyclohexanol (632 mg, 4 mmole) and NaH (60%,220 mg, 5.5 mmole) in 15 mL of anhydrous THF is refluxed for 0.5 hourbefore addition of 2-chloro-6,7-dimethoxyquinoxaline (674 mg, 3 mmole).The resulting mixture is continued to be refluxed for two hours. Theresidue after filtration and concentration is chromatographed on silicagel (ether) to provide acetic acidcis-4-(6,7-dimethoxyquinoxalin-2-yloxy)-cyclohexyl ester (m.p. 150-152°C.). Anal. Calcd. for C₁₈H₂₂N₂O₅: C, 62.42: H, 6.40; N, 8.09. Found: C,62.39; H. 6.55; N, 7.82 andcis-4-(6,7-dimethoxyquinoxalin-2-yloxy)-cyclohexanol (m.p. 148-150° C.).Anal. Calcd. for C₁₆H₂₀N₂O₄: C. 63.14; H, 6.62; N, 9.20; Found: C,62.80; H, 6.76; N, 8.67.

trans-4-(6,7-Dimethoxyquinoxalin-2-yloxy)-cyclohexanol [MS m/z: 304(M⁺)] is prepared similarly.

EXAMPLE 19 Dimethyl-carbamic acid4-(6,7-dimethoxyquinoxalin-2-yloxy)-cyclohexyl ester

A mixture of 4-(6,7-dimethoxyquinoxalin-2-yloxy)cyclohexanol (100 mg,0.33 mmole), dimethylcarbamyl chloride (90 μL, 1.2 mmole) and NaH (60%,19.6 mg, 0.49 mmole) in 5 mL of THF is stirred at room temperature forthree days to provide a white solid (m.p. 152-155° C.) isolated bychromatography (50% ethyl acetate/hexane). Anal. Calcd. for C₁₉H₂₅N₃O₅:C, 60.79; H. 6.71; N, 11.19; Found: C, 60.38; H, 6.54; N, 10.43.

EXAMPLE 20 3-Cyclohexyloxy-6,7-dimethoxyquinoxaline 1-oxide.

A mixture of 2-cyclohexyloxy-6,7-dimethoxyquinoxaline (110 mg. 0.38mmole) and meta-chlorobenzoic peracid (70%. 113 mg, 0.46 mmole) in 10 mLof methylene chloride is stirred at room temperature for one day. Thesolution after filtration is concentrated and the residue ischromatographed on silica gel (20% ethyl acetate/hexane) to provide thedesired product (m.p. 167-169° C.).trans-4-(6,7-Dimethoxy-4-oxy-quinoxalin-2-ylamino)-cyclohexanol (m.p.220-222° C.) is prepared similarly. Anal. Calcd. for C₁₆H₂₁N₃O₄•0.2 H₂O:C, 59.42; H, 6.69; N, 12.99; Found: C, 59.43; H, 6.64: N, 12.95.

EXAMPLE 21 Acetic acidtrans-4-(6,7-dimethoxyquinoxalin-2-ylamino)-cyclohexyl ester

A mixture of trans-4-(6,7-dimethoxyquinoxalin-2-ylamino)-cyclohexyl (303mg, 1 mmol), acetic anhydride (2 mL) and pyridine (2 mL) in 10 mL ofdichloromethane is stirred at room temperature overnight. The mixture isquenched with water (5 mL) and extracted with dichloromethane (2×30 mL).After drying over magnesium sulfate and filtration, the solution isconcentrated on a rotovap. The residue is chromatograplhed on silica gel(ethyl acetate) to provide the desired acetate as a light yellow solid(m.p. 176-177° C.). Anal. Calcd. for C₁₈H₂₃N₃O₄: C, 62.59; H, 6.71; N,12.17; Found: C, 62.89; H, 6.67; N, 11.95.

EXAMPLE 22(2exo,5exo)-5-(6,7-Dimethoxyquinoxaline-2-ylamino)-bicyclo[2.2.1heptan-2-ol

A mixture of (2exo,5exo)-5-aminobicyclo[2.2.1]heptan-2-acetate (127 mg,0.75 mmol) and 2-chloro-6,7-dimethoxyquinoxaline (224 mg, 1 mmol) isheated to 180° C. for six hours. After which time, the mixture is cooledto room temperature, dissolved in methylene chloride and purified viaflash column. The recovered product (20 mg, 7.5% yield) is dissolved inmethanol (2 mL), and a fresh solution of 1 N sodium methoxide (0.063 mL.0.063 mmol) is added. The reaction mixture is refluxed for ninetyminutes. The crude mixture is purified by preparative thin layerchromatography to provide the product as a yellow solid with a m.p. of97-100° C. C₁₇H₂₁N₃O₃ (m/z): 315.

The following compounds are prepared similarly beginning with theappropriate starting material(2endo,5exo)-5-(6,7-Dimethoxyquinoline-2-ylamino)-bicyclo[2.2.1]heptan-2-ol,as a yellow solid. C₁₇H₂₁N₃O₃ (m/z): 315. (2exo,6exo)-6-(6,7-Dimethoxy-quinolin-2-ylamino)-bicyclo[2.2.1]heptan-2-ol, asa yellow solid (30 mg, overall 21 %). C₁₇H₂₁N₃O₃ (m/z): 315. Anal.Calcd. for C₁₇H₂₁N₃O₃: C 64.74; H, 6.71; N, 13.32; Found C 58.42; H,6.26: N. 11.56.

EXAMPLE 23(2trans,4cis)-4-(6,7-Dimethoxyquinoxaline-2-ylamino)-2-methyl-cyclohexanoland(2trans,4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol

A mixture of 2-chloro-6,7-dimetlhoxy quinoxaline (1.08 g, 4.81 mmol )and (2trans)-4-amino-2-methylcyclohexanol (620 mg, 4.81 mmol) is heatedto 180° C. for six hours. The reaction yielded two diastereomers.

The major isomer is isolated as a yellow solid, assigned as (2trans,4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol (240mg, 0.76 mmol. C₁₇H₂₃N₃O₃ (m/z): 317. Anal. Calcd. for C₁₇H₂₃NO₃O₃•2H₂O:C 58.00; 1H, 7.69; N, 11.94; Found C 58.0; H, 6.58; N, 11.24.

The minor isomer is also a yellow solid, assigned as(2trans,4cis)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol,C₁₇H₂₃N₃O₃ (m/z): 317. Anal. Calcd. for C₁₇H₂₃N₃O₃•H₂O; C 60.08; H,6.94; N, 12.53; Found C 61.21; H. 6.94; N, 11.56.

The(2trans,4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanolis separated further by chiral HPLC into its individual enantiomers. Thefirst enantiomer has a (+)-rotation (elution order on Chiracel OJ). Thesecond enantiomer has a (−)-rotation (elution order on Chiracel OJ).Analytical conditions using a Chiracel OD column resulted in the (+)enantiomer elutinig second. The (−)-enantiomer exhibits a preferredactivity in a PDGF-R ELISA assay.

EXAMPLE 24(2cis,4cis)-4-(6,7-Dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanoland(2cis,4trans)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol

To a solution of a 2:1 mixture of(2trans,4trans)-4-(6,7-dimethoxy-quinoxalin-2-ylamino)-2-methyl-cyclohexanoland(2trans,4cis)-4-(6,7-dimethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol(120 mg, 0.38 mmol) in THF (7 mL) is added triphenylphosphine (110 mg,0.42 mmol) and diethyl azodicarboxylate (0.066 mL, 0.42 mmol) andbenzoic acid (46.4 mg, 0.38 mmol). The mixture is stirred at roomtemperature overnight and the residue after work-up is separated onsilica gel (30% ethyl acetate/hexane) to provide a mixture of benzoates.

To a solution of the major benzoate (50 mg, 0.12 mmol) in methanol (2mL) is added 1N sodium hydroxide (0.12 mL, 0.12 mmol). The pure product(13 mg, 32 % yield) is isolated from preparative thin layerchromatography as a yellow solid (m.p. 85-88° C.), assigned as(2cis,4cis)-4-(6,7-dimethoxy-quinoxalin-2-ylaminio)-2-methyl-cyclohexanol.C₁₇H₂₃N₃O₂ (m/z): 317.

Similarly the minor benzoate (4.4 mg) is hydrolyzed and the desiredproduct (3.3 mg, 100%) is also isolated from preparative thin layerchromatography as a yellow solid, assigned as(2cis,4trans)-4-(6,7-dimnethoxyquinoxalin-2-ylamino)-2-methyl-cyclohexanol.C₁₇H₂₃N₃O₃ (m/z): 317.

EXAMPLE 25(1R,2R,4S)-(+)-Bicyclo[2.2.1]hept-2-yl-(6,7-dimethoxyquinoxalin-2-yl)-amine

The (±)-bicyclo[2.2.1]hept-2-yl-(6,7-dimethoxyquinoxalin-2-yl)-amine ofExample 14 is resolved on a chiral HPLC column (Chiralpac AD. 25×2 cm,60% heptane/40% ethanol with 10 mM (1S)-(+)-camphorsulfonic acid, 12mL/minute) and the above titled product is obtained as the first eluent.The fractions collected are combined and washed with 50 mL of 1 N NaOHbefore drying (MgSO₄). The solution after filtration is concentrated ona rotovap and then dried under a high vacuum. A yellow solid obtained.[α]_(d) ²⁰ +19.5° (c=0.20, CH₂Cl₂) m.p. 184-186° C. Anal. calcd forC₁₇H₂₁N₃O₂×0.3 H₂O: C, 66.90 H, 7.15; N, 13.77. Found: C, 66.86; H,7.01; N, 13.86.

EXAMPLE 26 Biotransformative Preparation of(1S,2R,4S,5R)-5-(6,7-Dimethoxyquinoxalin-2-ylamino)-Bicyclo[2.2.1]heptan-2-ol

Fungi Strain F 2052 (Mortierella isabellina) is purchased from theNorthern Utilization Research and Development Division (NRRL).

The fungi is stored at −25° C. 250 mL conical flasks each containing 50mL seed culture medium (medium 216) are inoculated with 2 mL of fungisuspension and incubated on a rotary shaker (200 rpm at 23° C. for 3days. 250 mL conical flasks each containing 50 mL of the same mediumwere inoculated with mL of the seed culture and incubated on a rotaryshaker (200 rpm ) at 23° C. After 24 hours, (1R,2R,4)-(+)-Bicyclo[2.2.]hept-2-yl-(6,7-dimethoxyquinoxalin-2-yl)-amine ofExample 25 is dissolved in MeOH added to the flasks to a finalconcentration of 300 mg/L. The cultures are harvested after 24 hours ofincubation. (Medium 216: Glucose 0.4%, Yeast extract 0.05%, Soya flour0.05%, NaCI 0.05%, KH₂PO₄ 0.05.) The extraction is performed using 2volumes of acetonitrile, 1 volume de tert-butylmethyl ether and volumeof n-heptane were added to 1 volume of broth. After magnetic stirring at22° C, the extract separates to 3 layers. The intermediate layer iscollected and evaporated to dryness, and redissolved in ethyl acetate.The ethyl acetate extract is separated on silica gel (0.04-0.063 mm)using ethyl acetate as eluent. Fractions containing thebiotransformation product are separated on C1 8 silica using a H₂O/MeOHgradient as eluent. This chromatography yields the pure titled compoundas an amorphous yellow powder, m.p. 190-192° C.

EXAMPLE 27trans-4-[7-methoxy-6-(2-morpholin-4-yl-ethoxy)-quinoxalin-2-ylamino]-cyclohexanolandtrans-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinoxalin-2-ylamino]-cyclohexanol

The title compound is prepared by Mitsunobu coupling of6-hydroxy-7-methoxy-2-chloroquinoxaline:7-(2-morpholin-4-ylethoxy)-6-methoxy-2-chloroquinoxaline and2-(morpholin-4-yl)ethanol using the procedure of Example 1 and reactionof the resulting6-(2-morpholin-4-ylethoxy)-7-methoxy-2-chloroqtiinoxaline:7-(2-morpholin-4-ylethoxy)-6-methoxy-2-chloroquinoxaline and trans-4-amino-cyclohexanol using the procedure of Example 11.

EXAMPLE 282-[2-(trans-4-Hydroxy-cyclobexylamino)-7-metboxy-quinoxalin-6-yloxyl]-1-aceticacid and 2-[2-(trans-4-Hydroxy-cyclohexylamino)-6-methoxy-quinoxalin-7-yloxy]-1-aceticacid

The title compound is prepared by dealkylation of4-(6,7-dimethoxyquinoxaline-2-ylamino)cyclohexanol using the sodium saltof ethanethiol in DMF as described in Example 4, followed by alkylation)with bromoacetic acid in the presence of base as described in generalprocedure 6.

EXAMPLE 292-[2-(trans-4-Hydroxy-cyclohexylamino)-7-methoxy-quinoxalin-6-yloxyl]-N,N-dimethyl-acetamideand2-[2-(trans-4-Hydroxy-cyclohexylamino)-6-methoxy-quinoxalin-7-yloxyl]-N,N-dimethyl-acetamide

The title compound is prepared by aminolysis of the compound of Example28 using dimethylamine.

INTERMEDIATE EXAMPLE 1 4-Bromo-5-methoxy-benzene-1, 2-diaminedihydrochloride

To a solution of EtOAc (50 mL) and 5-bromo-4-methoxy-2-nitro-phenylamine(2.5 g, 10 mmol) under argon is added 5% Pd/C (0.5 g). The reactionmixture is hydrogenated at 50 psi for 1 hour. The mixture is filteredthrough Celite into a solution of HCl/IPA/EtOAc, and the pad is washedwith additional EtOAc. The resulting precipitate is filtered off toprovide white solid.

INTERMEDIATE EXAMPLE 2 7-Bromo-6-methoxy-quinoxalin-2-ol and6-Bromo-7-methoxy-quinoxalin-2-ol

To a solution of MeOH (15 mL) under argon is added pulverized NaOHpellets (0.86 g, 21 mmol) and 4-bromo-5-methoxy-benzene-1,2-diaminedihydrochloride (2.7 g, 9.3 mmol). The mixture is stirred for 10minutes, then a solution of 45% ethyl glyoxylate in toluene (2.7 g, 12mmol) is added portionwise. The reaction mixture is refluxed for 1 hour,then cooled. Water is added, then the suspension is filtered. Theresulting solid is washed successively with H₂O, MeOH, IPA, and Et₂O toprovide a yellow powder.

INTERMEDIATE EXAMPLE 3 7-Bromo-2-chloro-6-methoxy-quinoxaline and6-Bromo-2-chloro-7-methoxy-quinoxaline

To a mixture of 7-bromo-6-methoxy-quinoxalin-2-ol and6-bromo-7-methoxy-quinoxalin-2-ol (1 g, 3.9 mmol is added POCl₃ (5 mL).The reaction mixture is refluxed 1 hour, poured into ice water,filtered, then washed with water to provide a light-tan solid. Ratio of7-bromo-2-chloro-6-methoxy-quinoxaline:6-bromo-2-chloro-7-methoxy-quinoxaline is approximately 7:1 by ¹H NMR.

INTERMEDIATE EXAMPLE 4 5-Chloro-4-methoxy-2-nitroaniline

To a solution of N-(5-chloro-4-methoxy-2-nitrophenyl)-acetamide (2 g,8.2 mmol) in 5 N HCl (20 mL) is added 1,4-dioxane (10 mL), and themixture is stirred at 60° C. for 1.5 hours. The reaction mixture isconcentrated and partitioned between EtOAc/2 N NaOH. The aqueous layersare washed with EtOAc (3X), brine, dried (MgSO₄), adsorbed onto silicagel, and chromatographed (70% EtOAc/hexanes) to provide an orangepowder.

INTERMEDIATE EXAMPLE 5 4-Chloro-5-methoxy-benzene-1,2-diaminedihydrochloride

To a solution of EtOAc (25 mL) and5-chloro-4-methoxy-2-nitro-phenylarnine (1.6 g, 7.9 mmol) under argon isadded 5% Pd/(C (0.5 g). The reaction mixture is hydrogenated at 50 psifor 1 hour. The mixture is filtered under N₂ through Celite into asolution of 1 N HCl/Et₂O in EtOAc, and the pad is washed with additionalEtOAc. The resulting precipitate is filtered off to provide a whitesolid.

INTERMEDIATE EXAMPLE 6 7-Chloro-6-methoxy-quinoxalin-2-ol and6-Chloro-7-methoxy-quinoxalin-2-ol

To a solution of 4-chloro-5-methoxy-benzene-1,2-diamine dihydrochloride(1.8 g, 7.2 mmol) in EtOH (15 mL) under argon is added TEA (2.5 mL. 18mmol) at 0° C. The mixture is stirred for 20 minutes, then a solution of45% ethyl glyoxylate in toluene (2.1 g, 9.3 mmol) is added portionwise.The reaction mixture is warmed to room temperature, refluxed for 1.5hour, then cooled, water is added, then the suspension is filtered andwashed successively with H₂O, IPA, and Et₂O to provide a light-yellowpowder. The product is azeotroped several times with toluene and driedin vacuo before use.

INTERMEDIATE EXAMPLE 7 2,7-Dichloro-6-methoxy-quinoxaline and 2,6-Dichloro-7-methoxy-quinoxaline

To a mixture of 7-chloro-6--methoxy-quinoxalin-2-ol and6-chloro-7-methoxy-quinoxalin-2-ol (1 g, 4.7 mmol) under a CaCl₂ dryingtube is added POCl₃ (5 mL). The reaction mixture is refluxed 30 minutes,poured into cold saturated NaHCO₃ solution, filtered, then washed withwater to provide a solid. The ratio of2,7-dichloro-6-methoxy-quinoxaline: 2, 6-dichloro-7-methoxy-quinoxalineis approximately 6:1 by ¹H NMR.

INTERMEDIATE EXAMPLE 8 cis-4-Aminocyclohexanol

cis-4-aminocyclohexanol is made according to the literature procedurewith minor modification [J. Med. Chem. 18(6) 634 1975].

INTERMEDIATE EXAMPLE 9 exo-Bicyclo[2.2.1]hept-5-en -2-amine

exo-bicyclo[2.2.1]hept-5-en-2-amine is prepared with the same proceduresas in INTERMEDIATE EXAMPLE 15 from 5-norbornen-2-ol via a versatileintermediate exo-2-bicyclo[2.2.1]hept-5-en-2-yl isoindole-1,3-dione

INTERMEDIATE EXAMPLE 10 (2exo,6exo)-2-(6-Hydroxy-bicyclo[2.2.1]hept-2-yl isoindole-1,3-dione and(2exo, 5exo)-2-(5-hydroxy-bicyclo[2.2.1]hept-2-yl isoindole-1,3-dione

To a mixture of exo-2-bicyclo[2.2.1]hept-5-en-2-yl isoindole-1,3-dione(320 mg, 1.34 mmole) in 5 mL of THF at 0° C. is added a BH₃/THF solution(1 M, 2 mL, 2 mmole). The mixture is stirred at room temperature for twohours before addition of water (2 mL) and NaBO₃•4H₂O (900 mg). Theresulting suspension is stirred overnight. Ether (3×50 mL) is used toextract and dried over magnesium sulfate. The residue after filtrationand concentration is chromatographed on silica gel (ether) to providethe desired products which can be further separated.

INTERMEDIATE EXAMPLE 11 (2exo,5endo)-2-(5-Hydroxy-bicyclo[2.2.1]hept-2-yl isoindole-1,3-dione

(a): A mixture of (2exo, 6exo)-2-(6-hydroxy-bicyclo[2.2.1]hept-2-ylisoindole-1,3-dione and (2exo,5exo)-2-(5-hydroxy-bicyclo[2.2.1]hept-2-yl isoindole-1,3-dione (800 mg,3.3 mmole), and pyridinium chlorochromate (2 g) in 10 mL of methylenechloride is stirred at room temperature over the weekend. After beingdiluted with ether (100 mL), the suspension is filtered and the solutionis concentrated. The residue is chromatographed on silica gel (ether) togive 750 mg (95%) of the corresponding ketones. The ketones are furtherseparated by reverse phase HPLC (CH₃CN/H₂O, 10-70%) to provideexo-2-(5-oxy-bicyclo[2.2.1]hept-2-yl isoindole-1,3-dione.

(b): To a solution of exo-2-(5-oxy-bicyclo[2.2.1]hept-2-ylisoindole-1,3-dione (250 mg, 0.98 mmole) in 10 mL of methanol at 0° C.is added NaBH₄ (38 mg, 1 mmole). The mixture is stirred for additionalhalf-hour and quenched with 1 N HCl (1 mL). After being concentrated,the residue is extracted with methylene chloride (2×50 mL). Evaporationof methylene chloride gave the desired product used directly withoutfurther purification.

INTERMEDIATE EXAMPLE 12 (2endo, 5exo)-5-Amino-bicyclo[2.2.1]heptan-2-ol,(2exo, 5exo)-5-amino-bicyclo[2.2.1]heptan-2-ol, (2endo,6exo)-6-amino-bicyclo[2.2.1]heptan-2-ol, and (2exo,6exo)-6-amino-bicyclo[2.2.1]heptan-2-ol

The titled compounds are prepared from proper starting material byapplication of above procedure of INTERMEDIATE EXAMPLE 11.

INTERMEDIATE EXAMPLE 13 2-Methyl-6,7-dimethoxyquinoxaline

The title compound is prepared using an adaptation of the publishedmethod of Tamao, et al. Tetrahedron, 1982,38, 3347-3354. To a THFsolution under argon is added 2-Chloro-6,7-dimethoxyquinoxaline (5 g, 26mmol) and NiCl₂(dppp) (0.14 g, 0.26 mmol). The reaction mixture iscooled to 0° C., and a 3 M solution of MeMgBr in Et₂O (13 mL, 39 mmol)is added portionwise. The reaction mixture is allowed to warm to roomtemperature, stirred for 1 hour, then refluxed for 1.5 hours. Themixture is cooled, quenched with 10% HCl, stirred 10 minutes, then madebasic with 5% NaOH. CH₂Cl₂ and H₂O are added to the reaction, and themixture stirred overnight. Additional CH₂Cl₂H₂O, and NaCl are then addedand the mixture is filtered. The resulting solution is poured into aseparatoly funnel, and the aqueous layers are washed 3X with CH₂Cl₂. Theorganic layers are combined, washed with brine, dried (MgSO₄),concentrated onto silica gel, and chromatographed (50%-80%EtOAc/hexanes) to provide a orange solid (49% yield).

INTERMEDIATE EXAMPLE 14 6,7-Dimethoxy-2-quinoxaline carboxaldehyde

To a reaction flask under argon is added 1,4-dioxane (20 mL),2-methyl-6,7-dimethoxyquinoxaline (1.09 g. 5.3 mmol) and SeO₂ (1.8 g. 16mmol). The mixture is heated to 100° C. for 2 hours 45 minutes, cooled,and filtered through Celite. The pad is washed with portions of EtOAcand CH₂Cl₂. The resulting solution is concentrated, taken up inMeOH/CH₂Cl₂, loaded onto a silica gel column, and chromatographed (30%EtOAc/CH₂Cl₂) to provide an off-white solid (73% yield).

INTERMEDIATE EXAMPLE 15 (2exo,5exo)-5-Aminobicyclo[2.2.1]heptan-2-acetate

exo-5-Acetoxybicyclo[2.2.1]heptan-2-one andexo-6-acetoxybicyclo[2.2.1]heptan)-2-one are obtained from thebicyclo[2.2.1]hepta-2, 5-diene according to the procedure of R. Gagnon(J. Chem. Soc., Perkin trans. 1, 1505 1995) with minor modification.

To a solution of exo-5-acetoxybicyclo[2.2.1]heptan-2-one (350 mg. 2.08mmol) in 10 mL of THF at room temperature is added a 1 M borane/THFsolution (1.2 mL, 1.2 mmol). The mixture is stirred for 0.5 hour beforequenched at 0° C. with methanol (3 mL) and 1 N HCl (1.5 mL). Ethylacetate (3×30 mL) is used to extract and dried over magnesium sulfate.The residue after filtration and concentration is chromatographed onsilica gel to provide (2endo,5exo)-5-acetoxybicyclo [2.2.1]heptan-2-ol.

To a solution of (2endo,5exo)-5-acetoxybicyclo [2.2.1]heptan-2-ol (350mg, 2.06 mmol ) in THF (10 mL) is added phthalimide (454 mg, 3.09 mmol), triphenylphosphine (810 mg, 3.09 mmol) and diethyl azodicarboxylate(0.49 mL. 3.09 mmol ) at 0° C. The reaction is left to stir overnightand then is condensed on the rotovap and the residue is purified bycolumn chromatography (20% ethyl acetate/hexane) to provide the desiredproduct as a yellow solid.

A mixture of the above solid (300 mg, 1 mmol) and hydrazine (0.126 mL,2.2 mmol ) in 5 mL of methanol is heated to reflux for six hours. Afterremoval of methanol, dichloromethane (3×30 mL) is used to extract theresidue. Concentration of the solvent affords(exo,exo)-5-aminobicyclo[2.2.1]heptan-2-acetate (127 mg, 75%) which isused in the coupling reaction without further purification.

Similarly, (2endo,5exo)-5-aminobicyclo[2.2.1]heptan-2-acetate,(2endo,6exo)-6-aminobicyclo[2.2.1]heptan-2-acetate and(2exo,6exo)-6-aminobicyclo[2.2.1]heptan-2-acetate are prepared fromproper starting material.

INTERMEDIATE EXAMPLE 16 (2trans)-4-Amino-2-methylcyclohexanol

A mixture of 3-methyl-2-cyclohexenone (4 g, 36.36 mmol), toluenesulfonicacid (100 mg) and ethylene glycol (7 mL) in 100 mL of toluene isrefluxed overnight and water formed is removed by Dean-Stark trap. Theresidue after concentration is chromatographed on silica gel (10% ethylacetate/hexane) to give 3.36 g (62%) of7-methyl-1,4-dioxa-spiro[4.5]dec-7-ene.

To a stirred solution of 7-methyl-1,4-dioxa-spiro[4.5]dec-7-ene (3.36 g,22.47 mmol ) in tetrahydrofuran (THF) (125 mL) is added a 1 M solutionof borane in THF (22.47 mL, 22.47 mmol) at room temperature. The mixturestirred for one hour, and the reaction is quenched by adding H₂O (10 mL)at 0° C. followed by sodium perborate tetrahydrate (10.0 g, 66 mmol).The mixture is left to stir overnight. The two layers are separated. andthe aqueous layer is washed several times with ethyl acetate (4×150 mL).The desired alcohol is obtained as a clear liquid after flash columnchromatography.

The above alcohol (1.8 g, 10.5 mmol) is dissolved in methanol (50 mL)and 1 N HCl (16 mL). The reaction mixture is left to stir overnight. Theacidic solution is neutralized with 1 N sodium hydroxide (18 mL) andnormal aqueous work-up followed. The crude mixture is purified by flashcolumn (50% ethyl acetate) to give trans4-hydroxy-3-methyl-cyclohexanone.

To a solution of trans 4-hydroxy-3-methyl-cyclohexanone (780 mg, 6.1mmol) water (3 mL) is added hydroxylamine hydrochloride (550 mg, 7.92mmol), followed by the slow addition of a saturated solution of sodiumcarbonate (326 mg, 3.8 mmol) in water (1.02 mL). After stirring forthirty minutes, ether is added to the reaction mixture and the twolayers are separated. The organic layer is condensed and dissolved inethanol (10 mL). To the refluxing ethanol solution is added sodium (1.8g. 78.3 mmol ) over a period of one hour and the resulting mixture isheated for additional 2.5 hours. Afier removal of ethanol, n-propanol(10 mL), ether (25 mL), and water (3 mL) is added. The organic solutionis dried over magnesium sulfate and filtered. Concentration of solventsaffords a mixture of (2trans)-4-amino-2-methylcyclohexanol as a whitesolid.

INTERMEDIATE EXAMPLE 17 2-methoxy-4, 5-diaminiophenol dihydrochloride

The title compound is prepared by hydrogenation of 2-methoxy-4,5-dinitrophenol according to the procedure of Ehrlich et al., J. Org.Chem., 1947, 12, 522.

INTERMEDIATE EXAMPLE 18 7-hydroxy-6-methoxy-quinoxaline-2-ol and6-hydroxy-7-methoxy-quinoxaline-2-ol.

The title compounds are prepared from4-methoxy-5-hydroxybenzene-1,2-diamine dihydrochloride by reaction withNaOH and ethyl glyoxalate using the procedure of Intermediate Example 2.

INTERMEDIATE EXAMPLE 19 7-hydroxy-6-methoxy-2-chloroquinoxaline and6-hydroxy-7-methoxy-2-chloroquinoxaline

The title compounds are prepared from7-hydroxy-6-methoxy-quinoxaline-2-ol and6-hydroxy-7-methoxy-quinoxaline-2-ol by reaction with POCl₃ using theprocedure of Intermediate Example 3.

The compounds of formula I as described herein inhibit inhibition ofcell proliferation and/or cell matrix production and/or cell movement(chemotaxis) via inhibition of PDGF-R tyrosine kinase activity. A largenumber of disease states are caused by either uncontrolled reproductionof cells or overproduction of matrix or poorly regulated programmed celldeath (apoptosis). These disease states involve a variety of cell typesand include disorders such as leukemia, cancer, glioblastoma, psoriasis,inflammatory diseases, bone diseases, fibrotic diseases, atherosclerosisand occurring subsequent to angioplasty of the coronary, femoral orkidney arteries or, fibroproliferative disease such as in arthritis,fibrosis of the lung, kidney and liver. In particular, PDGF and PDGF-Rhave been reported to be implicated in specific types of cancers andtumors such as brain cancer, ovarian cancer, colon cancer, prostatecancer lung cancer, Kaposi's sarcoma and malignant melanoma. Inaddition, deregulated cellular proliferative conditions follow fromcoronary bypass surgery. The inhibition of tyrosine kinase activity isbelieved to have utility in the control of uncontrolled reproduction ofcells or overproduction of matrix or poorly regulated programmed celldeath (apoptosis).

This invention relates to the modulation and/or inhibition of cellsignaling, cell proliferation and/or cell matrix production and/or cellmovement (chemotaxis), the control of abnormal cell growth and cellinflammatory response. More specifically, this invention relates to theuse of substituted quinolinie and quinoxaline compounds which exhibitselective inhibition of differentiation, proliferation, matrixproduction, chemotaxis or mediator release by effectively inhibitingplatelet-derived growth factor-receptor (PDGF-R) tyrosine kinaseactivity.

Initiation of autophosphorylation, i.e., phosphorylation of the growthfactor receptor itself, and of the phosphorylation of a host ofintracellular substrates are some of the biochemical events which areinvolved in cell signaling, cell proliferation, matrix production,chemotaxis and mediator release.

By effectively inhibiting Lck tyrosine kinase activity, the compounds ofthis invention are also useful in the treatment of resistance totransplantation and autoimmujie diseases such as rheumatoid arthritis,multiple sclerosis and systemic lupus erythematosus, in transplantrejection, in graft vs. host disease, in hyperproliferative disorderssuch as tumours and psoriasis, and in diseases in which cells receivepro-inflammatory signals such as asthma, inflammatory bowel disease andpancreatitis. In the treatment of resistance to transplantation, acompound of this invention may be used either prophylactically or inresponse to an adverse reaction by the human subject to a transplantedorgan or tissue. When used prophylactically, a compound of thisinvention is administered to the patient or to the tissue or organ to betransplanted in advance of the transplantation operation. Prophylactictreatment may also include administration of the medication after thetransplantation operation but before any signs of adverse reaction totransplantation are observed. When administered in response to anadverse reaction, a compound of this invention is administered directlyto the patient in order to treat resistance to transplantation afteroutward signs of the resistance have been manifested.

According to a further feature of the invention there is provided amethod of inhibiting PDGF tyrosine kinase activity comprising contactinga compound according to claim 1 with a composition containing a PDGFtyrosine kinase.

According to a further feature of the invention there is provided methodof inhibiting Lck tyrosine kinase activity comprising contacting acompound according to claim 1 with a composition containing a Lcktyrosine kinase.

According to a further feature of the invention there is provided amethod for the treatment of a patient suffering from, or subject to,conditions which may be ameliorated or prevented by the administrationof an inhibitor of PDGF-R tyrosine kinase activity and/or Lck tyrosinekinase activity, for example conditions as hereinbefore described, whichcomprises the administration to the patient of an effective amount ofcompound of formula I or a composition containing a compound of formulaI, or a pharmaceutically acceptable salt thereof.

Reference herein to treatment should be understood to includeprophylactic therapy as well as treatment of established conditions.

The present invention also includes within its scope pharmaceuticalcompositions which comprise pharmaceutically acceptable amount of atleast one of the compounds of formula I in association with apharmaceutically acceptable carrier, for example, an adjuvant, diluent,coating and excipient.

In practice compounds or compositions for treating according to thepresent invention may administered in any variety of suitable forms, forexample, by inhalation, topically, parenterally, rectally or orally;more preferably orally. More specific routes of administration includeintravenous, intramuscular, subcutaneous, intraocular, intrasynovial,colonical, peritoneal, transepithelial including transdermal,ophthalmic, sublingual, buccal, dermal, ocular, nasal inhalation viainsufflation, and aerosol.

The compounds of formula I may be presented in forms permittingadministration by the most suitable route and the invention also relatesto pharmaceutical compositions containing at least one compoundaccording to the invention which are suitable for use as a medicament ina patient. These compositions may be prepared according to the customarymethods, using one or more pharmaceutically acceptable adjuvants orexcipients. The adjuvants comprise, inter alia, diluents, sterileaqueous media and the various non-toxic organic solvents. Thecompositions may be presented in the form of tablets, pills, granules,powders, aqueous solutions or suspensions, injectable solutions, elixirsor syrups, and may contain one or more agents chosen from the groupcomprising sweeteners such as sucrose, lactose, fructose, saccharin orNutrasweet® , flavorings such as peppermint oil, oil of wintergreen, orcherry or orange flavorings, colorings, or stabilizers such as methyl-or propyl-paraben in order to obtain pharmaceutically acceptablepreparations.

The choice of vehicle and the content of active substance in the vehicleare generally determined in accordance with the solubility and chemicalproperties of the product, the particular mode of administration and theprovisions to be observed in pharmaceutical practice. For example,excipients such as lactose, sodium citrate, calcium carbonate, dicalciumphosphate and disintegrating agents such as starch, alginic acids andcertain complex silica gels combined with lubricants such as magnesiumstearate, sodium lauryl sulfate and talc may be used for preparingtablets, troches, pills, capsules and the like. To prepare a capsule, itis advantageous to use lactose and liquid carrier, such as highmolecular weight polyethylene glycols. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance, tablets, pills, or capsules may be coatedwith shellac, sugar or both. When aqueous suspensions are used they maycontain emulsifying agents or agents which facilitate suspension.Diluents such as sucrose, ethanol, polyols such as polyethylene glycol,propylene glycol and glycerol, and chloroform or mixtures thereof mayalso be used. In addition, the active compound may be incorporated intosustained-release preparations and formulations.

For oral administration, the active compound may be administered, forexample, with an inert diluent or with an assimilable edible carrier, orit may be enclosed in hard or soft shell gelatin capsules, or it may becompressed into tablets, or it may be incorporated directly with thefood of the diet, or may be incorporated with excipient and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like.

For parenteral administration, emulsions, suspensions or solutions ofthe compounds according to the invention in vegetable oil, for examplesesame oil, groundnut oil or olive oil, or aqueous-organic solutionssuch as water and propylene olycol, injectable organic esters such asethyl oleate, as well as sterile aqueous solutions of thephannaceutically acceptable salts, are used. The injectable forms mustbe fluid to the extent that it can be easily syringed, and properfluidity can be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersion and by the use of surfactants. Prolonged absorption of theinjectable compositions can be brought about by use of agents delayingabsorption, for example, aluminum monostearate and gelatin. Thesolutions of the salts of the products according to the invention areespecially useful for administration by intramuscular or subcutaneousinjection. Solutions of the active compound as a free base orpharmacologically acceptable salt can be prepared in water suitablymixed with a surfactant such as hydroxypropyl-cellulose. Dispersion canalso be prepared in glycerol, liquid polyethylene glycols, and mixturesthereof and in oils. The aqueous solutions, also comprising solutions ofthe salts in pure distilled water, may be used for intravenousadministration with the proviso that their pH is suitably adjusted, thatthey are judiciously buffered and rendered isotonic with a sufficientquantity of glucose or sodium chloride and that they are sterilized byheating, irradiation, microfiltration, and/or by various antibacterialand antifungal agents, for example, parabens, chlorobutanol, phenol,sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and the freeze dryingtechnique which yield a powder of the active ingredient plus anyadditional desired ingredient from previously sterile-filtered solutionthereof.

Topical administration, gels (water or alcohol based), creams orointments containing compounds of the invention may be used. Compoundsof the invention may be also incorporated in a gel or matrix base forapplication in a patch, which would allow a controlled release ofcompound through transdermal barrier.

For administration by inhalation, compounds of the invention may bedissolved or suspended in a suitable carrier for use in a nebulizer or asuspension or solution aerosol, or may be absorbed or adsorbed onto asuitable solid carrier for use in a dry powder inhaler.

Solid compositions for rectal administration include suppositoriesformulated in accordance with known methods and containing at least onecompound of formula I.

Compositions according to the invention may also be formulated in amanner which resists rapid clearance from the vascular (arterial orvenous) wall by convection and/or diffusion, thereby increasing theresidence time of the viral particles at the desired site of action. Aperiadventitial depot comprising a compound according to the inventionmay be used for sustained release. One such useful depot foradministering a compound according to the invention may be a copolymermatrix, such as ethylene-vinyl acetate or a polyvinyl alcohol gelsurrounded by a Silastic shell. Alternatively, a compound according tothe invention may be delivered locally from a silicone polymer implantedin the adventitia.

An alternative approach for minimizing washout of a compound accordingto the invention during percutaneous, transvascular delivery comprisesthe use of nondiffusible. drug-eluting microparticles. Themicroparticles may be comprised of a variety of synthetic polymers, suchas polylactide for example, or natural substances, including proteins orpolysaccharides. Such microparticles enable strategic manipulation ofvariables including total dose of drug and kinetics of its release.Microparticles can be injected efficiently into the arterial or venouswall through a porous balloon catheter or a balloon over stent, and areretained in the vascular wall and the periadventitial tissue for atleast about two weeks. Formulations and methodologies for local,intravascular site-specific delivery of therapeutic agents are discussedin Reissen et al. (J Med. Coll. Cardiol. 1994; 23: 1234-244), the entirecontents of which are hereby incorporated by reference.

A composition according to the invention may also comprise a hydrogelwhich is prepared from any biocompatible or non-cytotoxic (homo orhetero) polymer, such as a hydrophilic polyacrylic acid polymer that canact as a drug absorbing sponge. Such polymers have been described forexample, in application WO 93/08845, the entire contents of which arehereby incorporated by reference. Certain of them, such as, inparticular, those obtained from ethylene and/or propylene oxide arecommercially available.

In the use of compounds according to the invention for treating,pathologies which are linked to hyperproliferative disorders, thecompounds according to the invention can be administered in differentways. For the treatment of restenosis, the compounds of the inventionare administered directly to the blood vessel wall by means of anangioplasty balloon which is coated with a hydrophilic film (for examplea hydrogel) which is saturated with the compound, or by means of anyother catheter containing an infusion chamber for the compound, whichcan thus be applied in a precise manner to the site to be treated andallow the compound to be liberated locally and efficiently at thelocation of the cells to be treated. This method of administrationadvantageously makes it possible for the compound to contact quickly thecells in need of treatment.

The treatment method of the invention preferably consists in introducinga compound according to the invention at the site to be treated. Forexample, a hydrogel containing composition can be deposited directlyonto the surface of the tissue to be treated, for example during asurgical intervention. Advantageously, the hydrogel is introduced at thedesired intravascular site by coating a catheter, for example a ballooncatheter, and delivery to the vascular wall, preferably at the time ofangioplasty. In a particularly advantageous manner, the saturatedhydrogel is introduced at the site to be treated by means of a ballooncatheter. The balloon may be chaperoned by a protective sheath as thecatheter is advanced toward the target vessel, in order to minimize drugwashoff after the catheter is introduced into the bloodstream.

Another embodiment of the invention provides for a compound according tothe invention to be administered by means of perfusion balloons. Theseperfusion balloons, which make it possible to maintain a blood flow andthus to decrease the risks of ischaemia of the myocardium, on inflationof the balloon, also enable the compound to be delivered locally atnormal pressure for a relatively long time, more than twenty minutes,which may be necessary for its optimal action. Alternatively, achannelled balloon catheter (“channelled balloon angioplasty, catheter”,Mansfield Medical, Boston Scientific Corp., Watertown, Mass.) may beused. The latter consists of a conventional balloon covered with a layerof 24 perforated channels which are perfused via an independent lumenthrough an additional infusion orifice. Various types of ballooncatheters, such as double balloon, porous balloon, microporous balloon,channel balloon, balloon over stent and hydrogel catheter, all of whichmay be used to practice the invention, are disclosed in Reissen et al.(1994), the entire contents of which are hereby incorporated byreference.

The use of a perfusion balloon catheter is especially advantageous, asit has the advantages of both keeping the balloon inflated for a longerperiod of time by retaining the properties of facilitated sliding and ofsite-specificity of the hydrogel, are gained simultaneously.

Another aspect of the present invention relates to a pharmaceuticalcomposition comprising a compound according to the invention andpoloxamer, such as Poloxamer 407 is a non-toxic, biocompatible polyol,commercially available (BASF, Parsippany, N.J.).

A poloxamer impregnated with a compound according to the invention maybe deposited directly on the surface of the tissue to be treated, forexample during a surgical intervention. Poloxamer possesses essentiallythe same advantages as hydrogel while having a lower viscosity.

The use of a channel balloon catheter with 3 poloxamer impregnated witha compound according to the invention is especially advantageous. Inthis case, the advantages of both keeping the balloon inflated for alonger period of time, while retaining the properties of facilitatedsliding, and of site-specificity of the poloxamer, are gainedsimultaneously.

The percentage of active ingredient in the compositions of the inventionmay be varied, it being necessary that it should constitute a proportionsuch that a suitable dosage shall be obtained. Obviously, several unitdosage forms may be administered at about the same time. A dose employedmay be determined by a physician or qualified medical professional, anddepends upon the desired therapeutic effect, the route of administrationand the duration of the treatment, and the condition of the patient. Inthe adult, the doses are generally from about 0.001 to about 50,preferably about 0.001 to about 5, mg/kg body weight per day byinhalation, from about 0.01 to about 100, preferably 0.1 to 70, moreespecially 0.5 to 10, mg/kg body weight per day by oral administration,and from about 0.001 to about 10, preferably 0.001 to 10, mg/kg bodyweight per day by intravenous administration. In each particular case,the doses are determined in accordance with the factors distinctive tothe patient to be treated, such as age, weight, general state of healthand other characteristics which can influence the efficacy of thecompound according to the invention.

The compounds/compositions according to the invention may beadministered as frequently as necessary in order to obtain the desiredtherapeutic effect. Some patients may respond rapidly to a higher orlower dose and may find much weaker maintenance doses adequate. Forother patients, it may be necessary to have long-tenn treatments at therate of 1 to 4 doses per day, in accordance with the physiologicalrequirements of each particular patient. Generally, the active productmay be administered orally 1 to 4 times per day. Of course, for otherpatients, it will be necessary to prescribe not more than one of twodoses per day.

The compounds of the present invention may also be formulated for use inconjunction with other therapeutic agents such as agents or inconnection with the application of therapeutic techniques to addresspharmacological conditions which may be ameliorated through theapplication of a compound of formula I, such as in the following:

The compounds of the present invention may be used in the treatment ofrestenosis post angioplasty using any device such as balloon, ablationor laser techniques. The compounds of the present invention may be usedin the treatment of restenosis following stent placement in thevasculature either as 1) primary treatment for vascular blockage, or 2)in the instance where angioplasty using any device fails to give apatent artery. The compounds of the present invention may be used eitherorally, by parenteral administration or the compound could be appliedtopically through the intervention of a specific device or as a properlyformulated coating on a stent device.

In one aspect the coating on a stent device is formed by applyingpolymeric material in which the compound of the invention isincorporated to at least one surface of the stent device.

Polymeric materials suitable for incorporating the compound of theinvention include polymers having relatively low processing temperaturessuch as polycaprolactone, poly(ethylene-co-vinyl acetate) or poly(vinylacetate or silicone gum rubber and polymers having similar relativelylow processing temperatures. Other suitable polymers includenondegradable polymers capable of carrying and delivering therapeuticdrugs such as latexes, urethanes, polysiloxanes,styrene-ethylene/butylene-styrene block copolymers (SEBS) andbiodegradable, bioabsorbable polymers capable of carrying and deliveringtherapeutic drugs, such as poly-DL-lactic acid (DL-PLA), andpoly-L-lactic acid (L-PLA), polyorthoesters, polyiminocarbonates,aliphatic polycarbonates, and polyphosphazenes.

A porosigen may also be incorporated in the drug loaded polymer byadding, the porosigen to the polymer along with the therapeutic drug toform a porous, drug loaded polymeric membrane. “Porosigen” means as anymoiety, such as microgranules of sodium chloride, lactose, or sodiumheparin, for example, which will dissolve or otherwise be degraded whenimmersed in body fluids to leave behind a porous network in thepolymeric material. The pores left by such porosignes can typically be alarge as 10 microns. The pores formed by porosignes such as polyethyleneglycol (PEG), polyethylene oxide/polypropylene oxide (PEO/PPO)copolymers, for example, can also be smaller than one micron, althoughother similar materials which form phase separations from the continuousdrug loaded polymeric matrix and can later be leached out by body fluidscan also be suitable for forming pores smaller than one micron. Thepolymeric material can be applied to the stent while the therapeuticdrug and porosigen material are contained within the polymeric material,to allow the porosigen to be dissolved or degraded by body fluids whenthe stent is placed in a blood vessel, or alternatively, the porosigencan be dissolved and removed from the polymeric material to form poresin the polymeric material prior to placement of the polymeric materialcombined with the stent within a blood vessel.

If desired, a rate-controlling membrane can also be applied over thedrug loaded polymer, to limit the release rate of the compound of theinvention. The rate-controlling membra)e can be added by applying acoating form a solution, or a lamination. The rate-controlling membraneapplied over the polymeric material can be formed to include a uniformdispersion of a porosigen in the rate-controlling membrane, and theporosigen in the rate-controlling membrane can be dissolved to leavepores in the rate-controlling membrane typically as large as 10 microns,or as small as 1 micron, for example, although the pores can also besmaller than 1 micron. The porosigen in the rate-controlling membranecan be, for example sodium chloride, lactose, sodium heparin,polyethylene glycol, polyethylene oxide/polypropylene oxide copolymers,and mixtures thereof.

In another aspect the coating on the stent device can be formed byapplying the compound of the invention to at least one surface of thestent device to form a bioactive laver and then applying one or morecoats of porous polymeric material over the bioactive layer, such thatthe porous polymeric material has a thickness adequate to provide acontrolled release of the compound.

In one aspect, the porous polymeric material is composed of a polyamide,parylene or a parylene derivative applied by catalyst-free vapordesposition. “Parylene” refers to a polymer based on p-xylylene and madeby vapor phase polymerization as described in U.S. Pat. No. 5,824,049,incorporated herein by reference.

Alternatively, the porous polymeric material is applied by plasmadeposition. Representative polymers suitable for plasm depositioninclude poly(ethylene oxide), poly(ethylene glycol), poly(propyleneoxide), and polymers of methane, silicone, tetrafluoroethylenetetramethyldisiloxane, and the like.

Other suitable polymer systems include polymers derived fromphotopolyimerizable monomers such as liquid monomers preferably havingat least two cross linkable C—C (Carbon to Carbon) double bonds, andbeing a non-gaseous addition polymerizable ethylenically unsaturatedcompound, having a boiling point above 100° C., at atmospheric pressure,a molecular weight of about 100-1500 and being capable of forming highmolecular weight addition polymers readily. More preferably, the monomeris preferably an addition photopolymerizable polyethylenicallyunsaturated acrylic or methacrylic acid ester containing two or moreacrylate or methacrylate groups per molecule or mixtures thereof.Representative examples of such multifuntional acrylates are ethyleneglycol diacrylate, ethylene glycol dimethacrylate, trimethylopropanetriacrylate, trimethylopropane trimethacrylate, pentaerythritoltetraacrylate or pentaerythritol tetramethacrylate, 1, 6-hexanedioldimethacrylate, and diethyleneglycol dimethacrylate.

Also useful in some special instances are monoacrylates such asn-butyl-acrylate, n-butyl methacrylate, 2-ethylhexyl acrylate,lauryl-acrylate, and 2-hydroxy-propyl acrylate. Small quantities ofamides of (meth)acrylic acid such as N-methylol methacrylamide butylether are also suitable, N-vinyl compounds such as N-vinyl pyrrolidone,vinyl esters of aliphatic monocarboxylic acids such as vinyl oleate,vinyl ethers of diols such as butanediol-1,4-divinyl ether and allylether and allyl ester are also suitable. Also included are othermonomers such as the reaction products of di- or polyepoxides such asbutanediol-1,4-diglycidyl ether or bisphenol A diglycidyl ether with(meth)acrylic acid. The characteristics of the photopolymerizable liquiddispersing medium can be modified for the specific purpose by a suitableselection of monomers or mixtures thereof.

Other useful polymer systems include a polymer that is biocompatible andminimizes irritation to the vessel wall when the stent is implanted. Thepolymer may be either a biostable or a bioabsorbable polymer dependingon the desired rate of release or the desired degree of polymerstability. Bioabsorbable polymers that could be used includepoly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone,polyorthoester, polyanhydride, polyvglycolic acid), poly(D,L-lacticacid), poly(glycolic acid-cotrimethylene carbonate), polyphosphoester,polyphosphoester urethane, poly(amino acids), cyanoacrylates,poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters)(e.g., PEO/PLA), polyalkylene oxlates, polyphoosphazenes andbiomolecules such as fibrin, fibrinogen, cellulose, starch, collagen andhyaluronic acid. Also, biostable polymers with a relatively low chronictissue response such as polyurethanes, silicones, and polyesters couldbe used and other polymers could also be used if they can be dissolvedand cured or polymerized on the stent such as polyolefins,polyisobutylene and ethylene-alphaolefine copolymers; acrylic polymersand copolymners, vinyl halide polymers and copolymers, such as polyvinylchloride; polyvinyl ethers, such as polyvinyl methyl ether;polvinylidene halides, such as polyvinylidene fluoride andpolyvinylidene chloride; polyacrylonitrile, polyvinyl ketones, polyvinylaromatics, such as polystyrene, polyvinyl esters, such as polyvinylacetate; copolymers of vinyl monomers with each other and olefins, suchas ethylene-methyl methacrylate copolymers, acrylonitril-styrenecopolyers, ABS resins, and ethylene-vinyl acetate copolymers;polyamides, such as Nylone 66 and polycaprolactam; alkyl reins,polycarbonates; polyoxymethylenes; polyimides, polyethers; epoxy reins,polyurethanes, rayon; rayon-triacetate; cellulose, cellulose acetate,cellulose butyrate; cellulose acetate buryrate; cellophane, cellulosenitrate; cellulose propionate; cellulose ethers; and carboxymethylcellulose.

In addition to plasma deposition and vapor phase deposition, othertechniques for applying the various coatings on the stent surfaces maybe employed. For example, a polymer solution may be applied to the stentand the solvent allowed to evaporate, thereby leaving on the stentsurface a coating of the polymer and the therapeutic substance.Typically, the solution can be applied to the stent by either sprayingthe solution onto the stent or immersing the stent in the solution.

The compounds of the present invention may be used in the treatment ofrestenosis in combination with any anticoagulant, antiplatelet,antithrombotic or profibrinolytic agent. Often patients are concurrentlytreated prior, during and after interventional procedures with agents ofthese classes either in order to safely perform the interventionalprocedure or to prevent deleterious effects of thrombus formation. Someexamples of classes of agents known to be anticoagulant, antiplatelet,antithrombotic or profibrinolytic agents include any formulation ofheparin, low molecular weight heparins, pentasaccharides, fibrinogenreceptor antagonists, thrombin inhibitors, Factor Xa inhibitors, orFactor VIIa inhibitors.

The compounds of the present invention may be used in combination withany antihypertensive agent or cholesterol or lipid regulating agent inthe treatment of restenosis or atherosclerosis concurrently with thetreatment of high blood pressure or atherosclerosis. Some examples ofagents that are useful in the treatment of high blood pressure includecompounds of the following classes; beta-blockers, ACE inhibitors,calcium channel antagonists and alpha-receptor antagonists. Someexamples of agents that are useful in the treatment of elevatedcholesterol levels or disregulated lipid levels include compounds knownto be HMGCoA reductase inhibitors, compounds of the fibrate class.

The compounds of the present invention may be used in the treatment ofvarious forms of cancer either alone or in combination with compoundsknown to be useful in the treatment of cancer.

It is understood that the present invention includes combinations ofcompounds of the present invention with one or more of theaforementioned therapeutic class agents

Compounds within the scope of the present invention exhibit markedpharmacological activities according to tests described in theliterature which tests results are believed to correlate topharmacological activity in humans and other mammals. The followingpharmacological in vitro and in vivo test results are typical forcharacterizing compounds of the present invention.

Preparation of Pharnaceutical Compositions and Pharmacological TestSection

Compounds within the scope of this invention exhibit significantactivity as protein tyrosine kinase inhibitors and possess therapeuticvalue as cellular antiproliferative agents for the treatment of certainconditions including psoriasis, atherosclerosis and restenosis injuries.Compounds within the scope of the present invention exhibit themodulation and/or inhibition of cell signaling and/or cell proliferationand/or matrix production and/or chemotaxis and/or cell inflammatoryresponse, and can be used in preventing or delaying the occurrence orreoccurrence of such conditions or otherwise treating the condition.

To determine the effectiveness of compounds of this invention, thepharmacological tests described below, which are accepted in the art andrecognized to correlate with pharmacological activity in mammals, areutilized. Compounds within the scope of this invention have beensubjected to these various tests, and the results obtained are believedto correlate to useful cellular differentiation mediator activity. Theresults of these tests are believed to provide sufficient infonnation topersons skilled in the pharmacological and medicinal chemistry arts todetermine the parameters for using the studied compounds in one or moreof the therapies described herein.

1. PDGF-R Tyrosine Kinase Autophosphorylation ELISA assay

The titled assay is performed as described by Dolle et al. (J. Med.Chem. 1994, 37, 2627), which is incorporated herein by reference, withthe exception of using the cell lysates derived from Human aortic smoothmuscle cells (HAMSC) as described below.

2. Mitogenesis Assay General Procedure

a. Cell Culture

Human aortic smooth muscle cells (passage 4-9) are plated in 96 wellplates in a growth supporting medium at 6000 cells/well and allowed togrow 2-3 days.

At approximately 85% confluence, cells are growth arrested with serumfree media (SFM).

b. Mitogenesis Assay

After 24 hour serum deprivation, medium is removed and replaced withtest compound/vehicle in SFM (200 μl/well). Compounds are solubilized incell culture DMSO at a concentration of 10 mM and further dilutions aremade in SFM.

After 30 min preincubation with compound, cells are stimulated with PDGFat 10 ng/mL. Determinations are performed in duplicate with stimulatedand unstimulated wells at each compound concentration.

Four hours later, 1 μCi ³H thymidine/well is added.

Cultures are terminated 24 hours after addition of growth factor. Cellsare lifted with trypsin and harvested onto a filter mat using anautomated cell harvester (Wallac MachII96). The filter mat is counted ina scintillation counter (Wallac Betaplate) to determine DNA-incorporatedlabel.

3. Chlemotaxis Assay

Human aortic smooth muscle cells (HASMC) at earlier passages areobtained from ATCC. Cells are grown in Clonetics SmGM 2 SingleQuots(media and cells at passages 4-10 are used. When cells are 80%confluent, a fluorescent probe, calcein AM (5 mM, Molecular Probe), isadded to the media and cells are incubated for 30 minutes. After washingwith HEPES buffered saline, cells are lifted with trypsin andneutralized with MCDB 131 buffer (Gibco) with 0.1% BSA, 10 mM glutamineand 10% fetal bovine serum. After centrifugation, cells are washed onemore time and resuspended in the same buffer without fetal bovine serumat 30000 cells/50 mL. Cells are incubated with different concentrationsof a compound of formula I (final DMSO concentration=1%) for 30 min at37° C. For chemotaxis studies, 96 well modified Boyden chambers(Neuroprobe, Inc.) and a polycarbonate membrane with 8 mm pore size(Poretics, Calif.) are used. The membrane is coated with collagen (SigmaC3657, 0.1 mg/mL). PDGF-pp (3 μng/mL) in buffer with and without acompound of formula I are placed in the lower chamber. Cells (30,000),with and without inhibitor, are placed in the upper chamber. Cells areincubated for 4 hours. The filter membrane is removed and cells on theupper membrane side are removed. After drying, fluoresce on the membraneis determined using Cytofluor II (Millipore) at excitation/emissionwavelengths of 485/530 nm. In each experiment, an average cell migrationis obtained from six replicates. Percent inhibition is determined fromDMSO treated control values. From five points concentration-dependentinhibitions, IC₅₀ value is calculated. Results are presented as amean±SEM from five such experiments.

4. EGF-Receptor Purification

EGF-receptor purification is based on the procedure of Yarden andSchiessinger. A431 cells are grown in 80 cm² bottles to confluency(2×10⁷ cells per bottle). The cells are washed twice with PBS andharvested with PBS containing 11.0 mmol EDTA (1 hour at 37° C., andcentrifuged at 600 g for 10 minutes. The cells are solubilized in 1 mLper 2×10⁷ cells of cold solubilization buffer (50 mmol Hepes buffer, pH7.6, 1% Triton X-100, 150 mmol NaCl, 5 mmol EGTA, 1 mmol PMSF, 50 mg/mLaprotinin, 25 mmol benzamidine, 5 mg/mL leupeptic, and 10 mg/mL soybeantrypsin inhibitor) for 20 minutes at 4° C. After centrifugation at100,000 g for 30 minutes, the supernatant is loaded onto a WGA-agarosecolumn (100 mL of packed resin per 2×10⁷ cells) and shaken for 2 hoursat 4° C. The unabsorbed material is removed and the resin washed twicewith HTN buffer (50 mmol Hepes, pH 7.6, 0.1% Triton X-100, 150 mmolNaCl), twice with HTN buffer containing 1 M NaCl, and twice with HTNGbuffer (50 mmol Hepes, pH 7.6, 0.1% Triton X-100, 150 mmol NaCl, and 10%glycerol). The EGF receptor is eluted batchwise with HTNG buffercontaining 0.5 M N-acetyl-D-glucosamine (200 mL per 2×10⁷ cells.). Theeluted material is stored in aliquots at −70° C. and diluted before usewith TMTNG buffer (50 mmol Tris-Mes buffer, pH 7.6. 0.1% Triton X-100,150 mmol NaCl, 10% glycerol).

5. Inhibition of EGF-R Autophosphorylation

A431 cells are grown to confluence on human fibronectin coated tissueculture dishes. After washing 2 times with ice-cold PBS, cells are lysedby the addition of 500 mL/ dish of lysis buffer (50 mmol Hepes, pH 7.5,150 mmol NaCl, 1.5 mmol MgCl₂, 1 mmol EGTA, 10% glycerol, 1% tritonX-100, 1 mmol PMSF, 1 mg/mL aprotinin, 1 mg/mL leupeptin) and incubating5 minutes at 4° C. After EGF stimulation (500 mg/mL 10 minutes at 37°C.) immunoprecipitation is performed with anti EGF-R (Ab 108) and theautophosphorylation reaction (50 mL aliquots, 3 mCi [g-³²P]ATP) sampleis carried out in the presence of 2 or 10 mM of compound of the presentinvention, for 2 minutes at 4° C. The reaction is stopped by adding hotelectrophoresis sample buffer. SDA-PAGE analysis (7.5% els) is followedby autoradiography and the reaction is quantitated by densitometryscanning of the x-ray films.

a. Cell Culture

Cells termed HER 14 and K721A are prepared by transfecting NIH3T3 cells(clone 2.2) (From C. Fryling, NCI, NIH), which lack endogenousEGF-receptors, with cDNA constructs of wild-type EGF-receptor or mutantEGF-receptor lacking tyrosine kinase activity (in which Lys 721 at theATP-binding site is replace by an Ala residue, respectively). All cellsare grown in DMEM with 10% calf sermm (Hyclone, Logan, Utah).

6. Selectivity vs. PKA and PKC is determined using commercial kits:

a. Pierce Colorimetric PKA Assay Kit, Spinzyme Format

Brief Protocol:

PKA enzyme (bovine heart) 1 U/assay tube

Kemptide peptide (dye labeled) substrate

45 minutes @ 30° C.

Absorbance at 570 nm

b. Pierce Colorimetric PKC Assay kit, Spinzyme Format

Brief Protocol:

PKC enzyme (rat brain) 0.025 U/assay tube

Neurogranin peptide (dye labeled) substrate

30 minutes @ 30° C.

Absorbance at 570 nm

7. p56^(lck) Tyrosine Kinase Inhibition Activity Measurements

p56^(lck) Tyrosine kinase inhibition activity is determined according toa procedure disclosed in U.S. Pat. No. 5,714,493, incorporated herein byreference.

In the alternative, the tyrosine kinase inhibition activity isdetermined according to the following method. A substrate(tyrosine-containing substrate.Biot-(βAla)₃-Lys-Val-Glu-Lys-Ile-Gly-Glu-Gly-Thr-Tyr-Glu-Val-Val-Tyr-Lys-(NH₂)recognized by P^(lck,) 1 μM) is first phosphorylated in presence orabsence of a given concentration of the test compound, by a given amountof enzyme (enzyme is produced by expression of P56^(lck) gene in a yeastconstruct) purified from a cloned yeast (purification of the enzyme isdone by following classical methods) in the presence of ATP (10 μM)MgC12(2.5 mM) MnC12 (2.5mM). NaCl (25 mM), DTT (0.4 mM) in Hepes 50 mM,pH 7.5, over 10 min at ambient temperature. The total reaction volume is50 μ, and the reactions are performed in a black 96-well fluoroplate.The reaction is stopped by addition of 150 μl of stopping buffer (100 mMHepes pH 7.5, KF 400 mM, EDTA 133 mM, BSA 1 g/l.) containing a selectedanti tyrosine antibody labelled with the Europium cryptate (PY20-K) at0.8 μg/ml and allophycocyanine-labelled streptavidin (XL665) at 4 μg/ml.The labelling of Streptavidin and anti-tyrosine antibodies wereperformed by Cis-Bio International (France). The mixture is countedusing a Packard Discovery counter which is able to measure time-resolvedhomogeneous fluorescence transfer (excitation at 337 nm, readout at 620nm and 665 nm). The ratio of the 665 nm signal/620 nm signal is ameasure of the phosphorylated tvrosine concentration. The blank isobtained by replacing enzyme by buffer. The specific signal is thedifference between the ratio obtained without inhibitor and the ratiowith the blank. The percentage of specific signal is calculated. TheIC₅₀ is calculated with 10 concentrations of inhibitor in duplicateusing Xlfit soft. The reference compound is staurosporine (Sigma) and itexhibits an IC₅₀ of 30±6 nM (n=20).

8. Measurement of In Vitro Tumor Inhibition

The inhibition of tumor growth in vitro by the compounds of thisinvention is determined as follows:

C6 rat glioma cell line (provided by ATCC) is grown as monolayers inDubelcco's Modified Eagle Medium containing 2 mM L-glutamine. 200 μg/mlpenicillin, 200 μg/ml streptomycin and supplemented with 10% (v/v) heatinactivated foetal calf serum. Cells in exponential phase of growth aretrypsinized, washed with PBS and diluted to a final concentration of6500 cells/ml in complete medium. Drug to be tested or control solventare added to the cell suspension (2.5 ml) under a volume of 50 μl and0.4 ml of 2.4% Noble Difco agar maintained at 45° C. are added andmixed. The mixture is immediately poured into Petri dishes and leftstanding for 5 minutes at 4° C. The number of cellular clones (>60cells) are measured after 12 days of incubation at 37° C. under 5% CO₂atmosphere. Each drug is tested at 10, 1, 0.1 and 0.01 μg/ml (finalconcentration in the agar) in duplicate. Results are expressed inpercent inhibition of clonogenicity relatively to untreated controls.IC₅₀'s are determined graphically from semi-logarithmic plots of themean value determined for each drug concentration.

9. Measurement of Tumor Inhibition In Vivo

The inhibition of tumor growth in vivo by the compounds of thisinvention is determined using a subucatenous xenograft model asdescribed in U.S. Pat. Nos. 5.700,823 and 5,760,066, in which mice areimplanted with C6 glioma cells and tumor growth is measured using veniercalipers.

The results obtained by the above experimental methods evidence that thecompounds within the scope of the present invention possess useful PDGFreceptor protein tyrosine kinase inhibition properties or p56^(lck)tyrosine kinase inhibition properties, and thus possess therapeuticvalue. The above pharmacological test results may be used to determinethe dosage and mode of administration for the particular therapy sought.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof.

We claim:
 1. A compound of formula I

wherein X is L₁OH or L₂Z₂; L₁ is (CR_(3a)R_(3b))_(r) or(CR_(3a)R_(3b))_(m)—Z₃—(CR_(3′a)R_(3′b))_(n); L₂ is(CR_(3a)R_(3b))_(p)—Z₄—-(CR_(3′a)R_(3′b))_(q) or ethenyl; Z₁ is CH; Z₂is optionally substituted hydroxycycloalkyl, optionally substitutedhydroxycycloalkenyl, optionally substituted hydroxyheterocycyl oroptionally substituted hydroxyheterocyclenyl; Z₃ is O, NR₄, S, SO orSO₂; Z₄ is O, NR₄, S, SO, SO₂ or a bond; m is 0 or 1; n is 2 or 3, andn+m=2or 3; p and q are independently 0,1,2,3 or 4, and p+q=0,1,2,3 or 4when Z₄ is a bond, and p+q=0,1,2 or 3 when Z₄ is other than a bond; r is2,3 or 4; R_(1a)and R_(1b) are independently optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl,hydroxy, acyloxy, optionally substituted alkoxy, optionally substitutedcycloalkyloxy, optionally substituted heterocyclyloxy, optionallysubstituted heterocyclylcarbonyloxy, optionally substituted aryloxy,optionally substituted heteroaryloxy, cyano, R₅R₆N or acylR₅N, or one ofR_(1a) and R_(1b) is hydrogen or halo and the other is optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionallysubstituted cycloalkyloxy, optionally substituted heterocyclyloxy,optionally substituted heterocyclylcarbonyloxy, optionally substitutedaryloxy, optionally substituted heteroaryloxy, cyano, R₅R₆N or acylR₅N.R_(1c) is hydrogen, optionally substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionallysubstituted alkoxy, optionally substituted cycloalkyloxy, optionallysubstituted heterocyclyloxy, optionally substitutedheterocyclylcarbonyloxy, optionally substituted aryloxy, optionallysubstituted heteroaryloxy, halo, cyano, R₅R₆N or acylR₅N; R_(3a),R_(3b), R_(3′b) are independently hydrogen or alkyl; R₄ is hydrogen,alkyl or acyl; and R₅ and R₆ are independently hydrogen or alkyl, or R₅and R₆ taken together with the nitrogen atom to which R₅ and R₆ areattached from azaheterocyclyl, or an N-oxide thereof, hydrate thereof,solvate thereof, prodrug thereof, or pharmaceutically acceptable saltthereof.
 2. The compound of claim 1 wherein L₁ is(CR_(3a)R_(3b))_(m)—Z₃Z—(CR_(3′a)R_(3′b))_(n); L₂ is(CR_(3a)R_(3b))_(p)—Z₄—(CR_(3′a)R_(3′b))_(q); Z₂ is optionallysubstituted hydroxycycloalkyl or optionally substitutedhydroxyheterocyclyl; Z₄ is O and NR₄; m is 0; n is 2or 3, p+q=0 or 1;R_(1a) and R_(1b) are independently optionally substituted alkyl,optionally substituted alkoxy, optionally substituted cycloalkyloxy,optionally substituted heterocyclyloxy or R₅R₆N, or one of R_(1a) andR_(1b) is hydrogen or halo and the other of R_(1a) and R_(1b) isoptionally substituted alkyl, optionally substituted alkoxy, optionallysubstituted cycloalkyloxy, optionally substituted heterocyclyloxy orR₅R₆N; R_(1c) is hydrogen, optionally substituted alkyl or optionallysubstituted alkoxy; R_(3a), R_(3b), R_(3′a) and R_(3′b) areindependently hydrogen or lower alkyl; R₄ is hydrogen; and R₅ and R₆taken together with the nitrogen atom to which R₅ and R₆ are attachedform azaheterocyclyl, or an N-oxide thereof, hydrate thereof, solvatethereof, prodrug thereof, or pharmaceutically acceptable salt thereof.3. The compound of claim 1 wherein X is L₂Z₂; L₁ is(CR_(3a)R_(3b))_(p)—Z₄—(CR_(3′a)R_(3′b))_(q); Z₂ is optionallysubstituted hydroxycycloalkyl; Z₄ is O and NR₄; p is 0; q is 0 or 1;R_(1a) and R_(1b) are independently optionally substituted alkyl,optionally substituted alkoxy, optionally substituted cycloalkyloxy oroptionally substituted heterocyclyloxy, or one of R_(1a) and R_(1b) ishydrogen or halo and the other of R_(1a) and R_(1b) is optionallysubstituted alkyl, optionally substituted alkoxy, optionally substitutedcycloalkyloxy or optionally substituted heterocyclyloxy; R_(1c) ishydrogen; R_(3′a) and R_(3′b) are independently hydrogen; and R₄ ishydrogen, or an N-oxide thereof, hydrate thereof, solvate thereof,prodrug thereof, or pharmuaceutically acceptable salt thereof.
 4. Thecompound of claim 1 wherein p and q are
 0. 5. The compound of claim 1wherein p+q=1.
 6. The compound of claim 1 wherein Z₄ is O.
 7. Thecompound of claim 1 wherein Z₄ is O, and p and q are
 0. 8. The compoundof claim 1 wherein Z₄ is O, and p+q=1.
 9. The compound of claim 1wherein Z₄ is NR₄.
 10. The compound of claim 1 wherein Z₄ is NR₄, and pand q are
 0. 11. The compound of claim 1 wherein Z₄ is NR₄, and p+q=1.12. The compound of claim 1 wherein Z₄ is S.
 13. The compound of claim 1wherein Z₄ is S, and p and q are
 0. 14. The compound of claim 1 whereinZ₄ is S, and p+q=1.
 15. The compound of claim 1 wherein R_(1a) andR_(1b) are independently optionally hydroxy substituted lower alkyl,hydroxy, lower alkoxy, cycloalkyloxy, heterocyclyloxy, or one of R_(1a)and R_(1b) is hydrogen or halo and the other of R_(1a) and R_(1b) isoptionally hydroxy substituted lower alkyl, hydroxy, lower alkoxy,cycloalkyloxy, heterocyclyloxy.
 16. The compound of claim 1 whereinR_(1a) and R_(1b) are independently optionally substitutedheterocyclylcarbonyloxy or optionally substituted lower alkoxy.
 17. Thecompound of claim 16 wherein the lower alkoxy is methoxy or ethoxy. 18.The compound of claim 1 wherein R_(1a) and R_(1b) are lower alkyl. 19.The compound of claim 18 wherein the lower alkyl is methyl or ethyl. 20.The compound of claim 1 wherein one of R_(1a) and R_(1b) is loweralkoxy, and the other of R_(1a) and R_(1b) is halo.
 21. The compound ofclaim 20 wherein the lower alkoxy is methoxy or ethoxy, and the halo ischloro or bromo.
 22. The compound of claim 1 wherein one of R_(1a) andR_(1b) is lower alkyl, and the other of R_(1a) and R_(1b) is loweralkoxy.
 23. The compound of claim 22 wherein the lower alkoxy is methoxyor ethoxy, and the lower alkyl is methyl or ethyl.
 24. The compound ofclaim 1 wherein one of R_(1a) and R_(1b) is lower alkoxy, and the otherof R_(1a) and R_(1b) is cycloalkyloxy.
 25. The compound of claim 24wherein the lower alkoxy is methoxy or ethoxy, and the cycloalkyloxy iscyclopentyloxy or cyclohecyloxy.
 26. The compound of claim 1 wherein oneof R_(1a) and R_(1b) is hydrogen, and the other of R_(1a) and R_(1b) islower alkoxy, cycloalkyloxy or heterocyclyloxy.
 27. The compound ofclaim 26 wherein the lower alkoxy is methoxy or ethoxy, and thecycloalkyloxy is cyclopentyloxy or cyclohexyloxy, and theheterocyclyloxy is furanyloxy.
 28. The compound of claim 1 whereinR_(1c) is hydrogen, lower alkyl or lower alkoxy.
 29. The compound ofclaim 28 wherein the lower alkyl is methyl or ethyl, and the loweralkoxy is methoxy or ethoxy.
 30. The compound of claim 1 wherein Z₂ ishydroxycycloalkyl optionally substituted with hydroxy or alkyl.
 31. Thecompound of claim 30 wherein Z₂ is hydroxycycloalkyl optionallysubstituted with lower alkyl.
 32. The compound of claim 16 wherein thelower alkoxy is optionally substituted with alkoxy, heterocyclyl,carboxy, alkoxycarbonyl or carbamoyl.
 33. The compound of claim 32wherein one of R_(1a) and R_(1b) is unsubstituted lower alkoxy and theother of R_(1a) and R_(1b) is optionally substitutedheterocyclylcarbonyloxy or lower alkoxy substituted with alkoxy,heterocyclyl, carboxy, alkoxycarbonyl or carbamoyl.
 34. The compound ofclaim 33 wherein one of R_(1a) and R_(1b) is methoxy and the other ofR_(1a) and R_(1b) is [1,4′]-bipiperadin-1′-ylcarbonyloxy,2-(ethoxy)ethoxy, 2-(4-morpholinyl)ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, carboxymethoxy, methoxycarbonylmethoxy, aminocarbonylmethoxy,N-methylaminocarbonylmethoxy or N,N-dimethylaminocarbonylmethoxy. 35.The compound according to claim 1 which is(2endo,5exo)-5-(6,7-Dimethoxyquinoline-2-ylamino) -bicyclo[2.2.1] heptan-2-ol; (2exo,6exo)-6-(6,7-Dimethoxyquinolin-2-ylamino) -bicyclo[2.2.1]heptan-2-ol; an N-oxide thereof, hydrate thereof, solvate thereof,prodrug thereof, or pharmaceutically acceptable salt thereof.
 36. Thecompound according to claim 1 which is4-(6,7-dimethoxyquinolin-3-ylamino)-cyclohexanol or an N-oxide thereof,hydrate thereof, solvate thereof, prodrug thereof, or pharmaceuticallyacceptable salt thereof.
 37. A pharmaceutical composition comprising acompound according to claim 1 and a pharmaceutically acceptable carrier.38. A method of inhibiting PDGF tyrosine kinase activity comprisingcontacting a compound according to claim 1 with a composition containingPDGF tyrosine kinase.
 39. A method of inhibiting Lck tyrosine kinaseactivity comprising contacting a compound according to claim 1 with acomposition containing a Lck tyrosine kinase.
 40. A method of inhibitingcell proliferation, differentiation, or mediator release in a patientsuffering from a disorder characterized by such proliferation and/ordifferentiation and/or mediator release comprising administering to apatient a pharmaceutically effective amount of a compound according toclaim
 1. 41. A method for treating a pathology linked to ahyperproliferative disorder, said method comprising administering to apatient in need of such treatment a pharmaceutically effective amount ofa compound according to claim
 1. 42. The method according to claim 41,wherein said pathology is restenosis.
 43. A method of treatingrestenosis comprising administering to a patient in need of suchtreatment a pharmaceutically effective amount of a compound according toclaim 1 at a predetermined site.
 44. The method according to claim 43,wherein said site of mechanical injury to an arterial wall produced bytreatment of an atherosclerotic lesion by angioplasty.
 45. The methodaccording to claim 43, wherein the compound according to claim 1 isadministered by means of an angioplasty balloon coated with ahydrophilic film saturated with the compound according to claim
 1. 46.The method according to claim 43, wherein the compound according toclaim 1 is administered by means of a catheter comprising an infusionchamber containing a solution of the compound according to claim
 1. 47.The method according to claim 43, wherein the compound according toclaim 1 is administered by means of a coating on a stent device, whereinthe coating comprises a compound according to claim
 1. 48. The methodaccording to claim 41 wherein the pathology linked to ahyperproliferative disorder is a cancer susceptible to treatment byinhibition of PDGF tryosine kinase.
 49. The method according to claim48, wherein the cancer is brain cancer, ovarian cancer, colon cancer,prostate cancer lung cancer, Kaposi's sarcoma or malignant melanoma. 50.A method for treating inflammation in a patient suffering from suchdisorder comprising administering to said patient an effective amount ofa compound according to claim 1.